The DOI matches its Crossref record; 110 of the 110 references it cites were found in a registry or an index; 53 of the 89 sources its claims cite were checked for support.
CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy
Open accessAbstract
Tauopathies, characterized by neurofibrillary tangles (NFTs) of phosphorylated tau proteins, are a group of neurodegenerative diseases, including frontotemporal dementia and both sporadic and familial Alzheimer's disease. Forebrain-specific over-expression of human tau(P301L), a mutation associated with frontotemporal dementia with parkinsonism linked to chromosome 17, in rTg4510 mice results in the formation of NFTs, learning and memory impairment and massive neuronal death. Here, we show that the mRNA and protein levels of NMNAT2 (nicotinamide mononucleotide adenylyltransferase 2), a recently identified survival factor for maintaining neuronal health in peripheral nerves, are reduced in rTg4510 mice prior to the onset of neurodegeneration or cognitive deficits. Two functional cAMP-response elements (CREs) were identified in the nmnat2 promoter region. Both the total amount of phospho-CRE binding protein (CREB) and the pCREB bound to nmnat2 CRE sites in the cortex and the hippocampus of rTg4510 mice are significantly reduced, suggesting that NMNAT2 is a direct target of CREB under physiological conditions and that tau(P301L) overexpression down-regulates CREB-mediated transcription. We found that over-expressing NMNAT2 or its homolog NMNAT1, but not NMNAT3, in rTg4510 hippocampi from 6 weeks of age using recombinant adeno-associated viral vectors significantly reduced neurodegeneration caused by tau(P301L) over-expression at 5 months of age. In summary, our studies strongly support a protective role of NMNAT2 in the mammalian central nervous system. Decreased endogenous NMNAT2 function caused by reduced CREB signaling during pathological insults may be one of underlying mechanisms for neuronal death in tauopathies.
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TL;DR
In rTg4510 tau P301L mice, NMNAT2 mRNA/protein and CREB activity decline in forebrain before neurodegeneration, and nmnat2 is a direct CREB target via two promoter CREs. Hippocampal overexpression of NMNAT1 or NMNAT2, but not NMNAT3, reduces tau-induced CA1 degeneration.
Key findings
- NMNAT2 protein in rTg4510 cortex and hippocampus was often reduced to <60% of age-matched controls at 1, 2, and 7 months; nmnat2 mRNA was significantly down-regulated in cortex at 1, 2, and 7 months and in hippocampus at 2 and 7 months, with no change in cerebellum.
- pCREB(Ser133), but not total CREB, was significantly reduced in 2-month-old rTg4510 cortex and hippocampus; pCREB/CREB ratios were ~50% of control, with no cerebellar difference. ChIP showed reduced pCREB occupancy at nmnat2 promoter regions containing CRE1+CRE2 and CRE2 alone in cortex and hippocampus, but not cerebellum.
- Two functional CREs were identified in the nmnat2 promoter. Forskolin increased Pro-2Kb luciferase activity almost 4-fold (2.9 ± 0.57% to 11.44 ± 1.62% normalized Renilla activity; P = 0.001), and mutating either CRE abolished induction; constitutively active CREB DIEDML increased Pro-2Kb activity (18.99 ± 1.9%; P < 0.001).
- rAAV overexpression of NMNAT1 or NMNAT2, but not NMNAT3, in rTg4510 hippocampi from 6 weeks reduced CA1 degeneration at 5 months: NMNAT1 stratum radiatum 156 ± 19% (P = 0.027) and stratum pyramidale 203 ± 36% (P = 0.029); NMNAT2 stratum radiatum 131 ± 13% (P = 0.047) and stratum pyramidale 154 ± 22% (P = 0.049). NMNAT2 also increased NF-M (207 ± 32%; P = 0.02), reduced cleaved caspase 3 (17 ± 12%; P = 0.01), GFAP (65 ± 13%; P < 0.05), CP-13/hTau (39 ± 7%; P < 0.01), and MC-1/hTau (42 ± 10%; P = 0.01).
Methods
- Used rTg4510 mice overexpressing human tau P301L and littermate controls; analyzed cortex, hippocampus, and cerebellum at 2 weeks, 1, 2, and 7 months by western blot and real-time qPCR, with ChIP for pCREB occupancy at the nmnat2 promoter.
- Tested nmnat2 promoter CRE function by luciferase reporter assays in 293T cells with wild-type or mutated CREs, pcDNA-CREB, dominant-negative CREB S133A, or constitutively active CREB DIEDML, with DMSO or 10 μM forskolin.
- Injected serotype 6 rAAV carrying human NMNAT1, NMNAT2, NMNAT3, or EGFP into rTg4510 and control hippocampi at 6 weeks; assessed neuroprotection at 5 months by EGFP/synapsin immunofluorescence, CA1 layer thickness, and western blot. Statistical analysis used Student’s t-test unless otherwise indicated, with P < 0.05 considered significant.
Limitations
- Stated: the authors note it remains to be determined whether NMNAT1 or NMNAT2 rescue of neurodegeneration can alleviate synaptic and cognitive deficits in rTg4510 mice; the mechanism of NMNAT neuroprotection is also unresolved, since NAD+ and NADH levels were unchanged and possible chaperone/clearance effects are discussed.
- Evident: neuroprotection was assessed mainly by CA1 layer thickness and selected protein markers rather than direct stereological neuron counts or behavioral outcomes; some analyses used small samples (e.g., n = 3 per genotype/age for qPCR, n = 3 per group for ChIP, and three animals for NMNAT2 western quantification).
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Claims the paper makes
60 Own result · 30 Own interpretation · 15 Supported · 10 Partly supported · 9 Supported so far · 5 No full text of the sources · 5 Own method · 1 Couldn’t confirm · 1 Sources not found · 1 Not checked yet · 1 No basis given · accuracy not yet measured
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“From 2.5 months onward, phosphorylated tau protein and neuronal loss can be detected in the forebrain of these mice (14,34,35).”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > NMNAT2 is down-regulated in the rTg4510 mouse brain prior to neurodegeneration
What the sources say
- Supportedcites [14] Spires, 2006, Region-specific dissociation of neuronal loss and neurofibrillary pathology in a mouse model of tauopathy, Am. J. Pathol. source
The neuron-loss results report loss in the dentate gyrus by 2.5 months. The age-related pathology section reports cells positive for CP13, a marker of phosphorylated tau, in CA1 and cortex at that age. These findings support detection of both changes in the forebrain from 2.5 months, though not necessarily in the same region. (LLM, conf=0.90)
- Partly supportedcites [34] Ramsden, 2005, Age-dependent neurofibrillary tangle formation, neuron loss, and memory impairment in a mouse model of human tauopathy (P301L), J. Neurosci. sourceExperimental — accuracy not yet measured
The Figure 2 caption reports phosphorylated-tau labeling in hippocampal neurons at 2.5 months. The age-dependent neurodegeneration section reports marked neuronal loss in 10-month-old mice, while the Discussion cites neuron counts at 5.5 months; neither establishes detectable neuronal loss from 2.5 months onward. Page numbers are unavailable in our copy. (LLM, conf=0.89)
- Not checked — no full text of the sourcecites [35] Santacruz, 2005, Tau suppression in a neurodegenerative mouse model improves memory function, Science source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
The cited sources that could be checked couldn’t confirm or dispute this claim.
In the paper
“The reduced abundance of two well-characterized CREB targets TrkB and cFos (52,53) provide further confirmation that CREBmediated transcription is reduced in rTg4510 mice (Supple- mentary Material, Fig. S3).”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > CREB activity is reduced in rTg4510 forebrains before the onset of cognitive dysfunction
What the sources say
- Not checked — no full text of the sourcecites [52] Flammer, 2006, Cyclic AMP response element-binding protein (CREB) and CAAT/enhancer-binding protein beta (C/EBPbeta) bind chimeric DNA sites with high affinity, Biochemistry source
- Could not verifycites [53] Zhang, 2005, Genome-wide analysis of cAMP-response element binding protein occupancy, phosphorylation, and target gene activation in human tissues, Proc. Natl Acad. Sci. USA sourceExperimental — accuracy not yet measured
The citation is attached to the description of TrkB and cFos as CREB targets; the reduction in rTg4510 mice is attributed to the citing paper’s supplementary figure. The Results and Promoter passages discuss CREB target genes generally, but searches for TrkB, cFos, and FOS found no passage identifying either named gene as a target. (LLM, conf=0.72)
boostedcorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“In rTg4510 mice (34,35), the age-dependent loss of neurons and progressive cognitive dysfunction closely mimic the clinical features of tauopathy.”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > INTRODUCTION
What the sources say
- Supportedcites [34] Ramsden, 2005, Age-dependent neurofibrillary tangle formation, neuron loss, and memory impairment in a mouse model of human tauopathy (P301L), J. Neurosci. source
The age-dependent neurodegeneration section reports marked forebrain atrophy and massive neuronal loss in older rTg4510 mice. The Discussion reports spatial-memory deficits beginning at 4.5 months and worsening with age, and describes the model’s tau pathology as highly comparable to human tauopathy. Page numbers were not supplied. (LLM, conf=0.92)
- Not checked — no full text of the sourcecites [35] Santacruz, 2005, Tau suppression in a neurodegenerative mouse model improves memory function, Science source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“No difference was found in the levels of P300, cREL or NFATc (data not shown), transcription factors that have been implicated in different neurodegeneration models (73 -76).”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > Reduced CREB signaling in rTg4510 mice
What the sources say
- Not checked — no full text of the sourcecites [73] Martin-Loeches, 2001, P300 amplitude as a possible correlate of frontal degeneration in schizophrenia, Schizophr. Res. source
- Supportedcites [74] Rouaux, 2003, Critical loss of CBP/p300 histone acetylase activity by caspase-6 during neurodegeneration, EMBO J. source
The citation supports the background statement that p300 is implicated in neurodegeneration models: the Introduction describes CBP/p300 changes in models of neuronal cell death, and the Discussion links loss of their function to neurodegeneration. The rTg4510 finding is marked “data not shown” in the citing sentence and is not attributed to this source. (LLM, conf=0.88)
- Supportedcites [75] Wu, 2010, Amyloid beta induces the morphological neurodegenerative triad of spine loss, dendritic simplification, and neuritic dystrophies through calcineurin activation, J. Neurosci. source
The citation supports the statement that NFATc has been implicated in a neurodegeneration model. The Discussion reports NFATc4 activation in Aβ-exposed neurons and says blocking NFAT activation protected against morphological deficits. The preceding finding of no difference in rTg4510 mice is marked “data not shown” and is not attributed to this source. (LLM, conf=0.91)
- Not checked — no full text of the sourcecites [76] Kogel, 2004, S100B potently activates p65/c-Rel transcriptional complexes in hippocampal neurons: Clinical implications for the role of S100B in excitotoxic brain injury, Neuroscience source
plain- Asserted: passes — The authors put it forward as true.
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The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“Mitochondria dysfunction has been demonstrated in tau P301L transgenic mice (92 -94)”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > Possible mechanisms of NMNAT neuroprotection
What the sources say
- Supportedcites [92] David, 2005, Proteomic and functional analyses reveal a mitochondrial dysfunction in P301L tau transgenic mice, J. Biol. Chem. source
The Abstract explicitly reports that functional analysis demonstrated mitochondrial dysfunction in P301L tau mice. The respiratory-defects section also reports reduced complex I activity in mitochondria from the transgenic mice. (LLM, conf=0.95)
- Supportedcites [93] Rhein, 2009, Amyloid-beta and tau synergistically impair the oxidative phosphorylation system in triple transgenic Alzheimer's disease mice, Proc. Natl Acad. Sci. USA source
The Discussion identifies pR5 mice as P301L tau transgenic mice and reports decreased mitochondrial complex I activity in pR5 mice at eight months. It also states that P301L mutant tau had previously been shown to induce mitochondrial dysfunction in these mice. The supplied copy does not provide page numbers. (LLM, conf=0.92)
- Not checked — no full text of the sourcecites [94] Perreault, 2009, Increased association between rough endoplasmic reticulum membranes and mitochondria in transgenic mice that express P301L tau, J. Neuropathol. Exp. Neurol. source
boosted- Asserted: passes — The authors put it forward as true.
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- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“pCREB levels are also reduced in 3xTg mice at 6 months of age (48).”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > Reduced CREB signaling in rTg4510 mice
What the sources say
- Supportedcites [48] Caccamo, 2010, CBP gene transfer increases BDNF levels and ameliorates learning and memory deficits in a mouse model of Alzheimer's disease, Proc. Natl Acad. Sci. USA source
The Results report that, in 6-month-old 3xTg-AD mice, hippocampal pCREB levels were about 40% lower at baseline than in age- and gender-matched NonTg mice. They were also significantly lower at every training time point analyzed. (LLM, conf=0.95)
plain- Asserted: passes — The authors put it forward as true.
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- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“NMNATs can also act as chaperones (21).”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > Possible mechanisms of NMNAT neuroprotection
What the sources say
- Supportedcites [21] Zhai, 2008, NAD synthase NMNAT acts as a chaperone to protect against neurodegeneration, Nature source
The paper states in its concluding passage (labeled Abstract in our copy; page not provided) that NMNAT functions as a chaperone independently of its enzymatic activity. It also reports chaperone activity for a human NMNAT homologue, supporting the plural phrasing. (LLM, conf=0.95)
plaindirect- Asserted: passes — The authors put it forward as true.
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- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“The neurodegeneration found in Drosophila NMNAT loss-of-function mutants (23) and cultured mouse ganglia neurons with reduced NMNAT2 expression (27) suggests that NMNATs are required to maintain neuronal integrity.”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > Exogenous expression of NMNAT1 or NMNAT2, but not NMNAT3, provides neuroprotection in rTg4510 hippocampi
What the sources say
- Supportedcites [23] Zhai, 2006, Drosophila NMNAT maintains neural integrity independent of its NAD synthesis activity, PLoS Biol. source
Citation (23) is attached to the Drosophila mutant finding, not the mouse-neuron finding attributed to citation (27). The Introduction states that loss of Drosophila nmnat causes severe neuronal and synaptic degeneration and concludes that NMNAT is required to maintain neuronal integrity; the Discussion likewise describes an essential neuronal protective function. No page numbers are provided in our copy. (LLM, conf=0.93)
- Supportedcites [27] Gilley, 2010, Endogenous Nmnat2 is an essential survival factor for maintenance of healthy axons, PLoS Biol. source
The Results section reports that reducing endogenous Nmnat2 in cultured mouse superior cervical ganglion neurons causes spontaneous neurite degeneration. The Discussion identifies Nmnat2 knock-down as evidence that the protein is required to maintain healthy axons. The Drosophila finding is attached to a different citation in the citing sentence. (LLM, conf=0.93)
hedgeddirect- Asserted: passes — The authors put it forward as true.
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- Supported
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Indeed, no change in the expression of cerebellar NMNAT2 was found at any of the ages examined (Fig. 1A and D).”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > NMNAT2 is down-regulated in the rTg4510 mouse brain prior to neurodegeneration
plain- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“At this age, neuronal loss was not yet observed.”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > NMNAT2 is down-regulated in the rTg4510 mouse brain prior to neurodegeneration
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Thus, the decrease in the NMNAT2 protein in rTg4510 mice was accompanied by a down-regulation of nmnat2 transcripts in the cortex at 1 month of age and older, and in the hippocampus at 2 months of age and older.”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > NMNAT2 is down-regulated in the rTg4510 mouse brain prior to neurodegeneration
plaincorrelational- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Strikingly, we found that the level of NMNAT2 in the cortex and hippocampi of rTg4510 mice was often reduced to ,60% of the level found in their agematched controls at 1, 2 and 7 months of age (Fig. 1A-C; Supplementary Material, Table S1).”
- Also stated in: § Abstract · boosted
“Here, we show that the mRNA and protein levels of NMNAT2 (nicotinamide mononucleotide adenylyltransferase 2), a recently identified survival factor for maintaining neuronal health in peripheral nerves, are reduced in rTg4510 mice prior to the onset of neurodegeneration or cognitive deficits.”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > NMNAT2 is down-regulated in the rTg4510 mouse brain prior to neurodegeneration
boostedcorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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- Also stated in: § Abstract · boosted
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Despite the reduction in NMNAT2 protein levels, there was no significant change in NAD + and NADH levels in the cortex or hippocampus of rTg4510 mice (Supplementary Material, Fig. S2).”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > NMNAT2 is down-regulated in the rTg4510 mouse brain prior to neurodegeneration
plain- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We found that nmnat2 transcription in rTg4510 mice was significantly down-regulated at 1, 2 and 7 months of age in the cortex and at 2 and 7 months of age in the hippocampus (Fig. 1E; Supplementary Material, Table S2).”
- Also stated in: § DISCUSSION · plain
“In this study, we found that nmnat2 transcription was significantly reduced in brain areas over-expressing tau P301L in 1-month-old rTg4510 mice, an FTDP-17 tauopathy animal model.”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > NMNAT2 is down-regulated in the rTg4510 mouse brain prior to neurodegeneration
plain- Asserted: passes — The authors put it forward as true.
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- Also stated in: § DISCUSSION · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“No down-regulation of nmnat2 transcription was seen in the cerebellum.”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > NMNAT2 is down-regulated in the rTg4510 mouse brain prior to neurodegeneration
plain- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The reduced NMNAT2 levels in the rTg4510 cortex and hippocampus at 1 month of age coincide with the time when tau P301L over-expression begins to reach its plateau.”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > NMNAT2 is down-regulated in the rTg4510 mouse brain prior to neurodegeneration
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“ChIP analysis in the wild-type brain demonstrated direct binding of pCREB to genomic regions containing both nmnat2 CRE sites as well as the single CRE2 region (Fig. 3B).”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > nmnat2 transcription is regulated in a CREB-dependent manner
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“No alterations in the levels of actin, NF-M or GFAP were observed in rTg4510 mice in the cerebellum, cortex or hippocampus (Fig. 1A; Supplementary Material, Table S1).”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > NMNAT2 is down-regulated in the rTg4510 mouse brain prior to neurodegeneration
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“This analysis identified two putative CREs close to the transcriptional start site (TSS) of the mouse nmnat2 gene (Fig. 3A).”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > nmnat2 transcription is regulated in a CREB-dependent manner
hedged- Asserted: passes — The authors put it forward as true.
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In the paper
“pCREB (Ser133) but not total CREB was significantly reduced in both the cortex and hippocampus of rTg4510 mice compared with control mice (Fig. 2A; Supplementary Material, Table S1).”
- Also stated in: § Abstract · hedged
“Both the total amount of phospho-CRE binding protein (CREB) and the pCREB bound to nmnat2 CRE sites in the cortex and the hippocampus of rTg4510 mice are significantly reduced, suggesting that NMNAT2 is a direct target of CREB under physiological conditions and that tau P301L overexpression down-regulates CREB-mediated transcription.”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > CREB activity is reduced in rTg4510 forebrains before the onset of cognitive dysfunction
plain- Asserted: passes — The authors put it forward as true.
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- Also stated in: § Abstract · hedged
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The widths of the stratum radiatum and stratum pyramidale of NMNAT1 over-expressing CA1 were significantly larger than the EGFP expressing side (Fig. 6E; stratum radiatum, 156 + 19%, P ¼ 0.027; stratum pyramidale, 203 + 36%, P ¼ 0.029).”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > Exogenous expression of NMNAT1 or NMNAT2, but not NMNAT3, provides neuroprotection in rTg4510 hippocampi
plaindirect- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“No detectable abnormality was caused by rAAV injections into control mice (Fig. 6A; n ¼ 5).”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > Exogenous expression of NMNAT1 or NMNAT2, but not NMNAT3, provides neuroprotection in rTg4510 hippocampi
plain- Asserted: passes — The authors put it forward as true.
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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“However, normal NAD and NADP levels were found in the cortex and hippocampus of rTg4510 mice.”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > Possible mechanisms of NMNAT neuroprotection
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“pCREB binds to both CRE1 + CRE2 and CRE2 containing regions in wild-type brain and 293T cells.”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > Chromatin immunoprecipitation (ChIP) analysis
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Almost all EGFP-positive cells were co-labeled with NeuN (Fig. 5B).”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > Exogenous expression of NMNAT1 or NMNAT2, but not NMNAT3, provides neuroprotection in rTg4510 hippocampi
plaincorrelationalSingle case- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Furthermore, the induction of luciferase activity seen with AG-CRE, Pro-2Kb or Pro-0.7Kbupon forskolin treatment was abolished in cells transfected with the dominant-negative pcDNA-CREB S133A , strongly suggesting the increase in luciferase activity was due to CREB phosphorylation.”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > nmnat2 transcription is regulated in a CREB-dependent manner
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In cells transfected with CREB DIEDML , high levels of luciferase activity were found in the cells transfected with AG CRE (38.63 + 3.2% of normalized Renilla luciferase activity; P , 0.001), Pro-2Kb (18.99 + 1.9% of normalized Renilla luciferase activity; P , 0.001) or Pro-0.7Kb(16.61 + 1.8% of normalized Renilla luciferase activity; P , 0.001) but not in cells transfected with a vector conta”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > nmnat2 transcription is regulated in a CREB-dependent manner
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“NMNAT2 abundance in the NMNAT2-rAAV-injected side was about twice the level found in the EGFP-rAAV side (Fig. 7A and B; ctrl, 100 + 30%; NMNAT2, 202 + 17%; P ¼ 0.02).”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > Exogenous expression of NMNAT1 or NMNAT2, but not NMNAT3, provides neuroprotection in rTg4510 hippocampi
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Consistent with this idea, we found that NMNAT2 overexpression in rTg4510 hippocampus significantly reduced the levels of hyperphosphorylated tau and tau with pathological conformation(s).”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > Possible mechanisms of NMNAT neuroprotection
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We identified two functional CREs proximal to the TSS of the mouse nmnat2 gene.”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > Reduced CREB signaling in rTg4510 mice
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“There was no difference in pCREB occupancy in rTg4510 cerebellum for either the promoter with CRE1 + CRE2 or CRE2 alone when compared with littermate controls (Fig. 4; Supplementary Material, Table S3).”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > nmnat2 transcription is regulated in a CREB-dependent manner
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Expressing NMNAT2 in the rTg4510 hippocampi significantly reduced CP-13 (Fig. 7F and G; the ratios of CP-13 to human tau: ctrl, 100 + 13%; NMNAT2, 39 + 7%; P , 0.01) and MC-1 (Fig. 7F and H; the ratios of MC-1 to human tau: ctrl, 100 + 13%; NMNAT2, 42 + 10%; P ¼ 0.01) immunoreactivity, compared with the control side expressing EGFP.”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > Exogenous expression of NMNAT1 or NMNAT2, but not NMNAT3, provides neuroprotection in rTg4510 hippocampi
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“No NMNAT1 immunoreactivity was detected in EGFP-positive cells within the EGFP-rAAV-injected side (Fig. 5D).”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > Exogenous expression of NMNAT1 or NMNAT2, but not NMNAT3, provides neuroprotection in rTg4510 hippocampi
plainSingle case- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The significant increase in NF-M in NMNAT2 over-expressing side (Fig. 7A and C; ctrl, 100 + 18%; NMNAT2, 207 + 32%; P ¼ 0.02) suggests that more neurons survived in rTg4510 hippocampi over-expressing NMNAT2.”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > Exogenous expression of NMNAT1 or NMNAT2, but not NMNAT3, provides neuroprotection in rTg4510 hippocampi
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“pCREB occupancy at the nmnat2 promoter is reduced in the cortex and hippocampus but not cerebellum of rTg4510 mice.”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > Chromatin immunoprecipitation (ChIP) analysis
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Binding was enriched in 293T cells upon forskolin treatment.”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > Chromatin immunoprecipitation (ChIP) analysis
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We found that pCREB(Ser133), but not total CREB levels, are reduced in rTg4510 mice prior to the onset of neurodegeneration.”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > Reduced CREB signaling in rTg4510 mice
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In our study, we found that over-expression of NMNAT1 and NMNAT2, but not NMNAT3, is neuroprotective in a mouse FTDP-17 model.”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > Over-expression of NMNAT2 and NMNAT1 reduce neurodegeneration in rTg4510 hippocampus
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Synapsin immunoreactivity is a valid estimate of neuronal morphology and anatomical integrity in rTg4510 mice.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In our study, we found that over-expression of NMNAT1 and NMNAT2, but not NMNAT3, is neuroprotective in a mouse FTDP-17 model.”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > Over-expression of NMNAT2 and NMNAT1 reduce neurodegeneration in rTg4510 hippocampus
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Synapsin immunoreactivity is a valid estimate of neuronal morphology and anatomical integrity in rTg4510 mice.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“rAAV vectors primarily transduce neurons.”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > Chromatin immunoprecipitation (ChIP) analysis
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Luciferase activity of cells transfected with vectors containing either AG CRE or nmnat2 promoter (Pro-2Kb or Pro-0.7Kb) was significantly increased upon forskolin treatment (Fig. 3C).”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > nmnat2 transcription is regulated in a CREB-dependent manner
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We found that pCREB(Ser133), but not total CREB levels, are reduced in rTg4510 mice prior to the onset of neurodegeneration.”
- Also stated in: § Chromatin immunoprecipitation (ChIP) analysis · plain
“pCREB levels are reduced in rTg4510 forebrains.”
- Also stated in: § Chromatin immunoprecipitation (ChIP) analysis · plain
“(A) Western blots show a reduction in the level of pCREB (Ser133), but not total CREB, in 2-month-old rTg4510 cortex and hippocampus compared with littermate controls.”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > Reduced CREB signaling in rTg4510 mice
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Also stated in: § Chromatin immunoprecipitation (ChIP) analysis · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“ChIP analysis demonstrated direct binding of pCREB to these CREs in mouse brains”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > Reduced CREB signaling in rTg4510 mice
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The luciferase activity driven by AG CRE was increased almost 3-fold from its basal level (17.79 + 0.08% of normalized Renilla luciferase activity) upon forskolin treatment (44.69 + 0.11% of normalized Renilla luciferase activity; P ¼ 0.011 between control and forskolin conditions).”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > nmnat2 transcription is regulated in a CREB-dependent manner
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In contrast, the hippocampi from NMNAT3-and EGFP-AAV injected hemispheres of rTg4510 mice were of similar size (Fig. 6D; n ¼ 6).”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > Exogenous expression of NMNAT1 or NMNAT2, but not NMNAT3, provides neuroprotection in rTg4510 hippocampi
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Mutating either one of the CRE sites located in nmnat2 promoter abolishes nmnat2 transcription.”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > Reduced CREB signaling in rTg4510 mice
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Using western blot analysis, we also observed reduced apoptosis and gliosis in the NMNAT2-injected hippocampus, compared with the control side.”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > Possible mechanisms of NMNAT neuroprotection
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In our study, we found that over-expression of NMNAT1 and NMNAT2, but not NMNAT3, is neuroprotective in a mouse FTDP-17 model.”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > Over-expression of NMNAT2 and NMNAT1 reduce neurodegeneration in rTg4510 hippocampus
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Synapsin immunoreactivity is a valid estimate of neuronal morphology and anatomical integrity in rTg4510 mice.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“NMNAT2 expression also offered substantial protection of the CA1 anatomical structures (Fig. 6E; stratum radiatum, 131 + 13%, P ¼ 0.047; stratum pyramidale, 154 + 22%, P ¼ 0.049).”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > Exogenous expression of NMNAT1 or NMNAT2, but not NMNAT3, provides neuroprotection in rTg4510 hippocampi
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Almost, no increase in luciferase activity was detected upon forskolin treatment if either or both of the CRE sites were mutated.”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > nmnat2 transcription is regulated in a CREB-dependent manner
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“and less pCREB bound to the nmnat2 promoter in the cortex and hippocampus of 2-month-old rTg4510 mice.”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > Reduced CREB signaling in rTg4510 mice
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Strong NMNAT1 immunoreactivity was detected in the nuclei of EGFP-positive neurons within the NMNAT1-rAAV-injected hippocampus (Fig. 5C).”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > Exogenous expression of NMNAT1 or NMNAT2, but not NMNAT3, provides neuroprotection in rTg4510 hippocampi
boostedSingle case- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Western blots show CP-13 (hyperphosphorylated tau), MC-1 (Tau with pathological conformation) and human Tau immunoreactivity in the hippocampus of rTg4510 mice over-expressing either EGFP-or N2-EGFP.”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > Chromatin immunoprecipitation (ChIP) analysis
plainn = 3- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Western blots show immunoreactivity of NMNAT2, NF-M, GFAP, actin, caspase 3 and activated cleaved caspase 3 in the hippocampus of rTg4510 mice overexpressing either EGFP-or NMNAT2-IRES-EGFP (N2-EGFP).”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > Chromatin immunoprecipitation (ChIP) analysis
plainn = 3 ·- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“the hippocampal CA1 and DG area appears larger on the NMNAT1 (B) or NMNAT2 (C) rAAV-injected side (B 1 , C 1 ) compared with the contralateral side injected with EGFP-rAAV (B 2 , C 2 ).”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > Chromatin immunoprecipitation (ChIP) analysis
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“No NMNAT1 is detected in CA1 in neurons infected with EGFP alone (D).”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > Chromatin immunoprecipitation (ChIP) analysis
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The specific reduction in nmnat2 expression in tau P301L overexpressing regions and the temporal correlation between nmnat2 down-regulation and tau P301L peak expression suggest that the pathological down-regulation of nmnat2 transcription is a direct consequence of tau P301L expression.”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > NMNAT2 is down-regulated in the rTg4510 mouse brain prior to neurodegeneration
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These data suggest that cAMP/ CREB signaling is impaired in rTg4510 brains prior to the onset of cognitive deficits.”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > CREB activity is reduced in rTg4510 forebrains before the onset of cognitive dysfunction
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“It is likely that a small change in CREB activity results in a rapid decline of nmnat2 levels.”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > Reduced CREB signaling in rTg4510 mice
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These data suggest that less pCREB binds to nmnat2 promoter in the brain regions of the rTg4510 mice that overexpress tau P301L .”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > nmnat2 transcription is regulated in a CREB-dependent manner
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In summary, we demonstrate that NMNAT2 is an important maintenance factor for mammalian brain health and its expression can be regulated through CREB-mediated transcription.”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > Possible mechanisms of NMNAT neuroprotection
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, exogenous NMNAT1 or 2 may be neuroprotective by reducing the level of toxic tau species.”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > Possible mechanisms of NMNAT neuroprotection
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These data suggest that the induction of luciferase activity results from the direct binding of pCREB to the nmnat2 CRE sites.”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > nmnat2 transcription is regulated in a CREB-dependent manner
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Taken together with the data from ChIP assay with wild-type mouse brains, we conclude that nmnat2 is a direct target of CREB signaling via two CREs proximal to the transcription start site in its promoter.”
- Also stated in: § Abstract · hedged
“suggesting that NMNAT2 is a direct target of CREB under physiological conditions”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > nmnat2 transcription is regulated in a CREB-dependent manner
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Also stated in: § Abstract · hedged
In the paper
“For example, the axon-protective function of NMNAT2 in cultured neurons derived from the superior cervical ganglia requires NAD synthesis activity (90).”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > Possible mechanisms of NMNAT neuroprotection
What the sources say
- Not checked — no full text of the sourcecites [90] Yan, 2010, Nmnat2 delays axon degeneration in superior cervical ganglia dependent on its NAD synthesis activity, Neurochem. Int. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These findings support the hypothesis that NMNAT-mediated chaperone activity promotes the clearance of toxic species.”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > Possible mechanisms of NMNAT neuroprotection
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Over-expression of NMNAT substantially reduces the formation of protein aggregates such as hAtx-1[82Q] protein in Drosophila.
In the paper
“In human AD brains, pCREB immunoreactivity was significantly decreased (70).”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > Reduced CREB signaling in rTg4510 mice
What the sources say
- Not checked — no full text of the sourcecites [70] Yamamoto-Sasaki, 1999, Impaired phosphorylation of cyclic AMP response element binding protein in the hippocampus of dementia of the Alzheimer type, Brain Res. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This is the first demonstration that NMNAT1 or NMNAT2, but not NMNAT3, over-expression provides neuroprotection in the mammalian brain.”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > DISCUSSION
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The downregulation of CREB activity in rTg4510 mice and the subsequent reduction in NMNAT2 could partially account for the cognitive deficits and neurodegeneration induced by tau P301L over-expression.”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > Reduced CREB signaling in rTg4510 mice
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In summary, our data suggest that cAMP/CREB signaling regulates nmnat2 transcription under physiological conditions.”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > nmnat2 transcription is regulated in a CREB-dependent manner
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Our data suggest that tau P301L over-expression impairs CREBmediated transcription and leads to a decrease in nmnat2 expression prior to the onset of neurodegeneration.”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > Reduced CREB signaling in rTg4510 mice
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The early reduction in both the total pCREB (Ser133) levels and the pCREB bound to the nmnat2 promoter in rTg4510 forebrain suggests that defective CREB-mediated transcription in rTg4510 brains accounts at least in part for reduced NMNAT2 expression.”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > DISCUSSION
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: The reduction in NMNAT2 protein levels in rTg4510 mice is primarily due to reduced nmnat2 transcription rather than altered protein stability.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These results suggest the direct binding and occupation of pCREB at the CRE sites in the nmnat2 promoter region.”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > nmnat2 transcription is regulated in a CREB-dependent manner
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, NMNAT2 overexpression reduces apoptosis and gliosis in rTg4510 hippocampi.”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > Exogenous expression of NMNAT1 or NMNAT2, but not NMNAT3, provides neuroprotection in rTg4510 hippocampi
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Nevertheless, our study provides the first evidence for a role of NMNATs in protecting against neurodegeneration in the mammalian CNS.”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > Over-expression of NMNAT2 and NMNAT1 reduce neurodegeneration in rTg4510 hippocampus
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We demonstrated CREB-dependent regulation of nmnat2 transcription through two CREB-binding sites in the nmnat2 promoter using a combination of ChIP and luciferase activity assays.”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > DISCUSSION
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The significant nmnat2 down-regulation in brain regions with tau P301L overexpression is likely to be a direct consequence of reduced CREB activity.”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > nmnat2 transcription is regulated in a CREB-dependent manner
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In summary, we demonstrate that NMNAT2 is an important maintenance factor for mammalian brain health and its expression can be regulated through CREB-mediated transcription.”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > Possible mechanisms of NMNAT neuroprotection
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Our data suggest that tau P301L over-expression impairs CREBmediated transcription and leads to a decrease in nmnat2 expression prior to the onset of neurodegeneration.”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > Reduced CREB signaling in rTg4510 mice
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Decreased endogenous NMNAT2 function caused by reduced CREB signaling during pathological insults may be one of underlying mechanisms for neuronal death in tauopathies.”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > Abstract
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“nmnat2 transcription is directly regulated by CREB.”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > Chromatin immunoprecipitation (ChIP) analysis
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Our data suggest that over-expression of NMNAT1 or NMNAT2, but not NMNAT3, is protective against hippocampal neuronal loss in rTg4510 mice.”
- Also stated in: § Abstract · plain
“We found that over-expressing NMNAT2 or its homolog NMNAT1, but not NMNAT3, in rTg4510 hippocampi from 6 weeks of age using recombinant adeno-associated viral vectors significantly reduced neurodegeneration caused by tau P301L over-expression at 5 months of age.”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > Exogenous expression of NMNAT1 or NMNAT2, but not NMNAT3, provides neuroprotection in rTg4510 hippocampi
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: The EGFP-rAAV-injected hemisphere provides a valid internal control for the effects of NMNAT-rAAV in rTg4510 mice.
- Also stated in: § Abstract · plain
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This interesting difference in NMNAT3 neuroprotection efficacy for peripheral nerve damage versus central tauopathy suggests that the distinct NMNATs may have distinct modes of protection in different forms of neurodegeneration.”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > Over-expression of NMNAT2 and NMNAT1 reduce neurodegeneration in rTg4510 hippocampus
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“NMNAT1 and NMNAT2 over-expression reduces neurodegeneration in Tau mice.”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > Chromatin immunoprecipitation (ChIP) analysis
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- It may state two separate claims as one. 26
- Probably not a substantial claim. 37
- The quote only partly states this claim. 1
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Substantial neurodegeneration is observed after 5 months of age, being most apparent in the hippocampal CA1 area (14,34,35).”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > NMNAT2 is down-regulated in the rTg4510 mouse brain prior to neurodegeneration
What the sources say
- Partly supportedcites [14] Spires, 2006, Region-specific dissociation of neuronal loss and neurofibrillary pathology in a mouse model of tauopathy, Am. J. Pathol. sourceExperimental — accuracy not yet measured
The section “rTg4510 Brain Suffers Dramatic Neuron Loss with Regional Vulnerability” reports that CA1 neuron loss begins by 5.5 months and reaches 82% by 8.5 months. But it does not identify CA1 as the most affected area: dentate gyrus loss begins earlier, at 2.5 months, and reaches 85% by 8.5 months. The supplied copy does not identify a page for these findings. (LLM, conf=0.88)
- Supportedcites [34] Ramsden, 2005, Age-dependent neurofibrillary tangle formation, neuron loss, and memory impairment in a mouse model of human tauopathy (P301L), J. Neurosci. source
The Age-dependent neurodegeneration section reports significantly lower brain weights from 5 months of age in rTg(tau P301L)4510 mice and says massive neuronal loss was most apparent in hippocampal CA1 in 10-month-old mice. The Discussion also describes marked CA1 neuron loss at 5.5 months, consistent with the claim’s timing. (LLM, conf=0.90)
- Not checked — no full text of the sourcecites [35] Santacruz, 2005, Tau suppression in a neurodegenerative mouse model improves memory function, Science source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“Three mammalian homologs, NMNAT1 -3, have been identified (24)(25)(26), with NMNAT2 (nicotinamide mononucleotide adenylyltransferase 2) being the most labile of the three isoforms with a half-life of ,4 h (27).”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > INTRODUCTION
What the sources say
- Supportedcites [24] Emanuelli, 2001, Molecular cloning, chromosomal localization, tissue mRNA levels, bacterial expression, and enzymatic properties of human NMN adenylyltransferase, J. Biol. Chem. source
The Results and Discussion section reports cloning a human NMNAT cDNA and confirming that it encodes NMNAT. This supports the paper’s use as one of the citations identifying mammalian NMNAT homologs. The NMNAT2 half-life is attributed to citation 27, not to this source. (LLM, conf=0.86)
- Not checked — no full text of the sourcecites [25] Raffaelli, 2002, Identification of a novel human nicotinamide mononucleotide adenylyltransferase, Biochem. Biophys. Res. Commun. source
- Supportedcites [26] Zhang, 2003, Structural characterization of a human cytosolic NMN/NaMN adenylyltransferase and implication in human NAD biosynthesis, J. Biol. Chem. source
The Results and Discussion section states that, together with the previously reported hsPNAT-1 and hsPNAT-2, this paper identifies three human PNAT isoenzymes. The approximately 4-hour half-life is attached to a separate citation (27), so it is not assessed against this source. (LLM, conf=0.93)
- Supportedcites [27] Gilley, 2010, Endogenous Nmnat2 is an essential survival factor for maintenance of healthy axons, PLoS Biol. source
The Results section, “Nmnat2 Is the Most Labile Nmnat Isoform,” directly compares the three isoforms and reports an in vitro half-life of less than 4 hours for Nmnat2, with minimal turnover of Nmnat1 and Nmnat3 over 72 hours. The cited source supports the part of the sentence attached to citation (27). (LLM, conf=0.93)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“transgenic mice expressing human mutated tau showed NFT formation and neuronal loss, implying a causal relationship between tau over-expression and neurodegeneration (8 -11).”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > INTRODUCTION
What the sources say
- Partly supportedcites [8] Gotz, 2001, Tau filament formation in transgenic mice expressing P301L tau, J. Biol. Chem. sourceExperimental — accuracy not yet measured
The Abstract reports neurofibrillary tangles in mice expressing human P301L tau, and the Results report cortical neurons undergoing apoptosis. The paper does not demonstrate neuronal loss in the mice; its Discussion mentions severe neuronal loss in human patients instead. It links the mouse pathology to the P301L mutation in combination with high expression, not to tau overexpression alone. (LLM, conf=0.87)
- Not checked — no full text of the sourcecites [9] Lewis, 2000, Neurofibrillary tangles, amyotrophy and progressive motor disturbance in mice expressing mutant (P301L) tau protein, Nat. Genet. source
- Not checked — no full text of the sourcecites [10] Andorfer, 2003, Hyperphosphorylation and aggregation of tau in mice expressing normal human tau isoforms, J. Neurochem. source
- Partly supportedcites [11] Yoshiyama, 2007, Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model, Neuron sourceExperimental — accuracy not yet measured
The paper’s Summary reports that P301S mutant human tau transgenic mice developed filamentous tau lesions followed by substantial neuron loss. But the Results report that mice expressing wild-type human tau at the same level showed no overt neurodegeneration up to 24 months. The findings therefore support a link involving mutant tau, not the broader implication that tau overexpression itself causes neurodegeneration. (LLM, conf=0.88)
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
- Partly supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“In rTg4510 mice (34,35), tau with the mis-sense mutation P301L, found in some FTDP-17 cases (36), is over-expressed in the forebrain driven by the calcium-calmodulin kinase II (CaMKII) promoter.”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > NMNAT2 is down-regulated in the rTg4510 mouse brain prior to neurodegeneration
What the sources say
- Supportedcites [34] Ramsden, 2005, Age-dependent neurofibrillary tangle formation, neuron loss, and memory impairment in a mouse model of human tauopathy (P301L), J. Neurosci. source
The “Generation of transgenic mice expressing mutant human tau P301L” section describes the P301L tau responder transgene and a CaMKII-promoter activator transgene. It reports high expression primarily in forebrain structures, especially the hippocampus and cortex. The supplied passages do not give page numbers. (LLM, conf=0.94)
- Not checked — no full text of the sourcecites [35] Santacruz, 2005, Tau suppression in a neurodegenerative mouse model improves memory function, Science source
- Not checked — no full text of the sourcecites [36] Hutton, 1998, Association of missense and 5′-splice-site mutations in tau with the inherited dementia FTDP-17, Nature source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
- Supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“However, neuronal loss appears to be independent of tangle formation in some transgenic mouse models (12)(13)(14).”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > INTRODUCTION
What the sources say
- Not checked — no full text of the sourcecites [12] Wittmann, 2001, Tauopathy in Drosophila: neurodegeneration without neurofibrillary tangles, Science source
- Supportedcites [13] Andorfer, 2005, Cell-cycle reentry and cell death in transgenic mice expressing nonmutant human tau isoforms, J. Neurosci. source
The Discussion (page not provided) reports that some dying neurons in the htau transgenic mouse lacked neurofibrillary tangles. It concludes that tangle toxicity may not be the only cause of neuronal loss in this model, supporting the claim's qualified wording. (LLM, conf=0.92)
- Supportedcites [14] Spires, 2006, Region-specific dissociation of neuronal loss and neurofibrillary pathology in a mouse model of tauopathy, Am. J. Pathol. source
The Discussion (p. 1605) explicitly states that neuron loss can occur before, and therefore independently of, neurofibrillary pathology in the rTg4510 mouse model. The Abstract likewise reports neuronal loss before lesions appeared in the dentate gyrus. This supports the claim's qualified reference to some transgenic mouse models. (LLM, conf=0.94)
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Every source the paper cites for this claim was checked and supports it.
In the paper
“Reducing NMNAT2 levels in cultured mouse superior cervical ganglia neurons induced Wallerian-like degeneration, suggesting that NMNAT2 is required to maintain axonal health in the peripheral nervous system (27).”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > INTRODUCTION
What the sources say
- Supportedcites [27] Gilley, 2010, Endogenous Nmnat2 is an essential survival factor for maintenance of healthy axons, PLoS Biol. source
The Results section, “Nmnat2 Knock-Down Induces Wallerian-Like Degeneration,” reports that siRNA knock-down of Nmnat2 in cultured mouse SCG neurons caused neurite degeneration and identifies it as Wallerian-like. It concludes that endogenous Nmnat2 is required to prevent spontaneous degeneration of SCG neurites, supporting the claim about axonal maintenance in this peripheral-neuron model. (LLM, conf=0.94)
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Mutant tau expression starts around postnatal day 7 and peaks at 1 month of age (34,35).”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > NMNAT2 is down-regulated in the rTg4510 mouse brain prior to neurodegeneration
What the sources say
- Partly supportedcites [34] Ramsden, 2005, Age-dependent neurofibrillary tangle formation, neuron loss, and memory impairment in a mouse model of human tauopathy (P301L), J. Neurosci. sourceExperimental — accuracy not yet measured
The ‘Generation of transgenic mice expressing mutant human tau P301L’ section reports that transgenic tau was first detected at postnatal day 7, supporting the onset part of the claim. Neither that passage nor the Figure 1 caption states that expression peaks at one month; the caption identifies P7 as the earliest expression shown by the postnatal forebrain immunoblot. (LLM, conf=0.86)
- Not checked — no full text of the sourcecites [35] Santacruz, 2005, Tau suppression in a neurodegenerative mouse model improves memory function, Science source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Partly supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“Several tau mutations linked to FTDP-17 have been identified (2 -7)”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > INTRODUCTION
What the sources say
- Not checked — no full text of the sourcecites [2] Hutton, 2000, Molecular genetics of chromosome 17 tauopathies, Ann. N. Y. Acad. Sci. source
- Not checked — no full text of the sourcecites [3] Spillantini, 1998, Tau protein pathology in neurodegenerative diseases, Trends Neurosci. source
- Not checked — no full text of the sourcecites [4] Sperfeld, 1999, FTDP-17: an early-onset phenotype with parkinsonism and epileptic seizures caused by a novel mutation, Ann. Neurol. source
- Not checked — no full text of the sourcecites [5] Bugiani, 1999, Frontotemporal dementia and corticobasal degeneration in a family with a P301S mutation in tau, J. Neuropathol. Exp. Neurol. source
- Not checked — no full text of the sourcecites [6] Poorkaj, 2001, Frequency of tau gene mutations in familial and sporadic cases of non-Alzheimer dementia, Arch. Neurol. source
- Supportedcites [7] Goedert, 2005, Mutations causing neurodegenerative tauopathies, Biochim. Biophys. Acta source
Section 4, “Mutations in Tau,” states that 32 different tau mutations had been described in over 100 families with FTDP-17. This directly supports the claim that several linked mutations have been identified. (LLM, conf=0.95)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Every source the paper cites for this claim was checked and supports it.
In the paper
“Over-expression of NMNAT, on the other hand, provides neuroprotection against several degenerative conditions in Drosophila (21,23).”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > INTRODUCTION
What the sources say
- Supportedcites [21] Zhai, 2008, NAD synthase NMNAT acts as a chaperone to protect against neurodegeneration, Nature source
The passage labeled Abstract describing the Drosophila SCA1 model reports that NMNAT overexpression suppresses degenerative phenotypes and provides some protection against expanded human ataxin-1. Another Abstract passage describes protection against activity-induced neurodegeneration and delayed axonal degeneration, supporting the claim that it protects against several degenerative conditions in Drosophila. (LLM, conf=0.93)
- Supportedcites [23] Zhai, 2006, Drosophila NMNAT maintains neural integrity independent of its NAD synthesis activity, PLoS Biol. source
The Results section, “Overexpression of nmnat Protects against Excessive Activity-Induced Neurodegeneration,” reports protection in two retinal degeneration mutants and in flies exposed to constant intense light. The Discussion, “Maintaining Neuronal Integrity,” likewise identifies these as distinct conditions in which overexpression protects against degeneration. (LLM, conf=0.94)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Loss of nmnat in the Drosophila eye causes rapid neuronal degeneration (23).”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > INTRODUCTION
What the sources say
- Supportedcites [23] Zhai, 2006, Drosophila NMNAT maintains neural integrity independent of its NAD synthesis activity, PLoS Biol. source
The Results section, “Loss of nmnat Causes Severe Early-Onset Neuronal Degeneration,” reports defects in mutant eyes by two days of age that worsen with age. It concludes that loss of nmnat causes severe degeneration throughout photoreceptor neurons. (LLM, conf=0.94)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“In mammals, over-expressing NMNATs significantly delays Wallerian degeneration of peripheral nerves (28)(29)(30)(31)(32)(33).”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > INTRODUCTION
What the sources say
- Partly supportedcites [28] Press, 2008, Nmnat delays axonal degeneration caused by mitochondrial and oxidative stress, J. Neurosci. sourceExperimental — accuracy not yet measured
The Introduction (page unavailable) reports delayed Wallerian degeneration after nerve injury in Wldˢ mutant mice and explains that the protective chimeric protein contains Nmnat1. It also says increased Nmnat expression delayed axonal degeneration in cultured dorsal root ganglion neurons. The paper does not establish that overexpressing NMNATs themselves significantly delays Wallerian degeneration of peripheral nerves in mammals. (LLM, conf=0.85)
- Not checked — no full text of the sourcecites [29] Araki, 2004, Increased nuclear NAD biosynthesis and SIRT1 activation prevent axonal degeneration, Science source
- Partly supportedcites [30] Wang, 2005, A local mechanism mediates NAD-dependent protection of axon degeneration, J. Cell Biol. sourceExperimental — accuracy not yet measured
Figure 2 in Results and discussion reports that overexpressing Nmnat1 significantly delayed Wallerian degeneration (P < 0.001). Materials and methods identifies the model as cultured rat dorsal root ganglion explants, not intact peripheral nerves. The paper tests Nmnat1 and a fusion protein containing it, rather than NMNATs generally. (LLM, conf=0.88)
- Partly supportedcites [31] Sasaki, 2010, Axonal degeneration is blocked by nicotinamide mononucleotide adenylyltransferase (NMNAT) protein transduction into transected axons, J. Biol. Chem. sourceExperimental — accuracy not yet measured
The opening section says Nmnat1 overexpression can delay axonal degeneration, and Results and Discussion reports axonal protection in transgenic mice expressing Nmnat proteins. The paper’s own experiments use cultured dorsal-root-ganglion neurons; our copy does not establish the more specific claim that overexpression significantly delays Wallerian degeneration of peripheral nerves in vivo. (LLM, conf=0.84)
- Supportedcites [32] Sasaki, 2009, Transgenic mice expressing the Nmnat1 protein manifest robust delay in axonal degeneration in vivo, J. Neurosci. source
The Results section reports that overexpression of cytNmnat1 delayed Wallerian degeneration in the distal sciatic nerve of transgenic mice after transection. Seven days after injury, those nerves showed no evidence of axon loss or myelin debris, unlike wild-type nerves. This supports the claim for a mammalian peripheral nerve, specifically the mouse sciatic nerve. (LLM, conf=0.93)
- Partly supportedcites [33] Yahata, 2009, Nicotinamide mononucleotide adenylyltransferase expression in mitochondrial matrix delays Wallerian degeneration, J. Neurosci. sourceExperimental — accuracy not yet measured
In the Results section on transgenic overexpression (Figs. 2–3), NMNAT3-overexpressing mice showed a significant delay in degeneration of transected sciatic nerves. The claim generalizes this effect to NMNATs, but the same section reports no detectable delay in NMNAT1-overexpressing mice. (LLM, conf=0.88)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Cognitive impairment in spatial reference memory and synaptic dysfunction in hippocampal CA1 pyramidal neurons begin to manifest at 4.5 months of age (37).”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > NMNAT2 is down-regulated in the rTg4510 mouse brain prior to neurodegeneration
What the sources say
- Supportedcites [37] Hoover, 2010, Tau mislocalization to dendritic spines mediates synaptic dysfunction independently of neurodegeneration, Neuron source
The Results section reports spatial reference-memory impairment in 4.5-month-old rTgP301L (rTg4510) mice, but not at 1.3 months. It also reports impaired LTP in hippocampal CA1 only at 4.5 months, supporting the claim of synaptic dysfunction there. Page numbers are not provided in our copy. (LLM, conf=0.92)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“NAD + is used to synthesize NADP + , whose reduced form NADPH is involved in defense against oxidative stress (91).”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > Possible mechanisms of NMNAT neuroprotection
What the sources say
- Supportedcites [91] Pollak, 2007, The power to reduce: pyridine nucleotides—small molecules with a multitude of functions, Biochem. J. source
The NADK section states that NADP is synthesized by phosphorylation of NAD, supporting NAD+ as its precursor. The Conclusion states that NADPH has a key role in oxidative defence systems. Page numbers are not available in our copy. (LLM, conf=0.94)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“The protective effects occurring in these mice are attributed to a chimeric gene Ube4b/NMNAT1, which encodes an in-frame fusion protein of the amino-terminal of ubiquitination factor E4B (UBE4B) and the complete coding region of NMNAT1 (83,84).”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > Over-expression of NMNAT2 and NMNAT1 reduce neurodegeneration in rTg4510 hippocampus
What the sources say
- Partly supportedcites [83] Conforti, 2000, A Ufd2/D4Cole1e chimeric protein and overexpression of Rbp7 in the slow Wallerian degeneration (WldS) mouse, Proc. Natl Acad. Sci. USA sourceExperimental — accuracy not yet measured
The Results identify a WldS-specific in-frame fusion of the N-terminal 70 amino acids of Ufd2 and the C-terminal 302 amino acids of D4Cole1e. The Abstract and Discussion call it a promising candidate for slowing Wallerian degeneration, not an established cause of protection. Our copy does not identify D4Cole1e as NMNAT1 or say that the fusion contains NMNAT1’s complete coding region. (LLM, conf=0.88)
- Not checked — no full text of the sourcecites [84] Mack, 2001, Wallerian degeneration of injured axons and synapses is delayed by a Ube4b/Nmnat chimeric gene, Nat. Neurosci. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“NMNATs are essential enzymes for NAD biosynthesis and several studies have found the enzymatic activity to be important for their neuroprotective effect (reviewed in 81,89).”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > Possible mechanisms of NMNAT neuroprotection
What the sources say
- Supportedcites [81] Coleman, 2010, Wallerian degeneration, wld(s), and nmnat, Annu. Rev. Neurosci. source
In “The WldS Gene and Protein” (page not supplied), the review identifies Nmnat1 as a key enzyme in the NAD+ salvage pathway and says other Nmnat isoforms synthesize NAD+. In “Defining Protective Domains in the Molecule and the Cell” (page not supplied), it reports several studies in which disrupting Nmnat1 enzymatic activity severely reduced or abolished WldS-mediated neuroprotection. (LLM, conf=0.91)
- Supportedcites [89] Zhai, 2009, Nicotinamide/nicotinic acid mononucleotide adenylyltransferase, new insights into an ancient enzyme, Cell Mol. Life Sci. source
The Introduction describes NMNAT as central to NAD biosynthesis. In “The role of NAD synthesis activity of NMNAT in neuroprotection,” the review reports that numerous mutational studies suggest its enzymatic activity is required for neuroprotection. It also notes a conflicting Drosophila result, which does not negate the claim that several studies found the activity important. (LLM, conf=0.93)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Ab oligomers also cause tau mislocalization (77,78).”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > Reduced CREB signaling in rTg4510 mice
What the sources say
- Could not verifycites [77] Ittner, 2010, Dendritic function of tau mediates amyloid-beta toxicity in Alzheimer's disease mouse models, Cell sourceExperimental — accuracy not yet measured
The Introduction says Aβ injections exacerbate tau phosphorylation and tangles, while the Discussion describes tau’s dendritic role in mediating Aβ toxicity. Neither passage says that Aβ oligomers cause tau to mislocalize. Searches for oligomers, tau missorting, and Aβ-induced changes in tau localization did not establish that causal link in our copy. (LLM, conf=0.74)
- Supportedcites [78] Zempel, 2010, Abeta oligomers cause localized Ca(2+) elevation, missorting of endogenous Tau into dendrites, Tau phosphorylation, and destruction of microtubules and spines, J. Neurosci. source
The Results section, “Aβ oligomers induce missorting of Tau,” reports that treating mature hippocampal neurons with Aβ oligomers redistributed Tau into the somatodendritic compartment. This directly supports the claim that Aβ oligomers cause Tau mislocalization. (LLM, conf=0.94)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Could not verify
Every source the paper cites for this claim was checked and supports it.
In the paper
“NMDAR (N-methyl-D-aspartate receptors)-mediated calcium influx is known to increase pCREB levels through several signaling pathways (65).”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > Reduced CREB signaling in rTg4510 mice
What the sources say
- Supportedcites [65] Lonze, 2002, Function and regulation of CREB family transcription factors in the nervous system, Neuron source
The passage labeled Abstract (page unavailable) describes NMDA receptors as calcium-permeable channels and calcium–calmodulin signaling to a CREB kinase. Another passage reports CREB phosphorylation following NMDA receptor activation and says different signaling pathways control its duration, supporting the citing sentence’s broad paraphrase. (LLM, conf=0.84)
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Genetic manipulations that decrease CREB-mediated transcription lead to deficits in both synaptic plasticity and long-term memory, whereas overexpression of CREB results in memory enhancements (38).”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > Reduced CREB signaling in rTg4510 mice
What the sources say
- Supportedcites [38] Lee, 2009, The molecular and cellular biology of enhanced cognition, Nat. Rev. Neurosci. source
The “CREB and C/EBPs” section directly states that genetic manipulations decreasing CREB transcription in mice cause deficits in LTP and long-term memory, while CREB overexpression in flies, mice, and rats enhances memory. LTP is a form of synaptic plasticity, so the citing sentence accurately paraphrases the passage. (LLM, conf=0.94)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Removing the creb1 gene in adult mouse forebrain or chronic inhibition of CREB function leads to extensive neurodegeneration in the hippocampus (67,68).”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > Reduced CREB signaling in rTg4510 mice
What the sources say
- Not checked — no full text of the sourcecites [67] Mantamadiotis, 2002, Disruption of CREB function in brain leads to neurodegeneration, Nat. Genet. source
- Partly supportedcites [68] Valor, 2010, Ultrastructural and transcriptional profiling of neuropathological misregulation of CREB function, Cell Death Differ. sourceExperimental — accuracy not yet measured
The section “Chronic inhibition of CREB function causes dark neuron degeneration” reports CA1 neuron loss in mice expressing the CREB inhibitor A-CREB, supporting the chronic-inhibition part of the sentence. The passages do not report removal of the creb1 gene in adult mouse forebrain, so this source does not support that part. (LLM, conf=0.88)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“In the CNS, Wld S has been shown to protect nigrostriatal axons from degeneration in a model of Parkinson's disease, to reduce the number of axonal spheroids in mice with gracile axonal dystrophy, and to protect axons from neuronal degeneration induced by toxic insults (85)(86)(87).”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > Over-expression of NMNAT2 and NMNAT1 reduce neurodegeneration in rTg4510 hippocampus
What the sources say
- Not checked — no full text of the sourcecites [85] Gillingwater, 2004, Neuroprotection after transient global cerebral ischemia in Wld(s) mutant mice, J. Cereb. Blood Flow Metab. source
- Supportedcites [86] Sajadi, 2004, Wlds-mediated protection of dopaminergic fibers in an animal model of Parkinson disease, Curr. Biol. source
This source supports the Parkinson’s-disease clause of the sentence; the other two clauses have separate citations. In Results and Discussion (page not provided), WldS mice showed significantly greater preservation of striatal dopaminergic fibers than controls after a 6-OHDA lesion of the nigrostriatal pathway. (LLM, conf=0.92)
- Not checked — no full text of the sourcecites [87] Mi, 2005, The slow Wallerian degeneration gene, WldS, inhibits axonal spheroid pathology in gracile axonal dystrophy mice, Brain source
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“CREB is also important for cell survival (65,66).”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > Reduced CREB signaling in rTg4510 mice
What the sources say
- Supportedcites [65] Lonze, 2002, Function and regulation of CREB family transcription factors in the nervous system, Neuron source
In “CREB Family Members and Neuronal Survival,” the paper reports that CREB-mediated gene expression is necessary and sufficient for survival of multiple neuronal subtypes in vitro, and that genetic studies demonstrate a requirement for CREB in the survival of certain neurons. It also states directly that CREB is central to cell survival. The citing sentence’s broad phrasing is consistent with this account, though the evidence discussed is neuronal. (LLM, conf=0.94)
- Not checked — no full text of the sourcecites [66] Bito, 2003, Ca(2+)/CREB/CBP-dependent gene regulation: a shared mechanism critical in long-term synaptic plasticity and neuronal survival, Cell Calcium source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Interestingly, NMNAT over-expression can prevent axonal damage resulting from exogenous application of oxidants (28).”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > Possible mechanisms of NMNAT neuroprotection
What the sources say
- Supportedcites [28] Press, 2008, Nmnat delays axonal degeneration caused by mitochondrial and oxidative stress, J. Neurosci. source
In the section “Nmnat3 prevents oxidant-induced axonal degeneration,” the authors report that Nmnat3-expressing neurons showed no evidence of axonal degeneration after oxidant treatment. The Discussion also states that Nmnat proteins inhibited axonal degeneration caused by external oxidants. (LLM, conf=0.94)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“The role of NMNATs in neuroprotection was first implicated in studies using Wallerian Slow mice (Wld S ; reviewed in 81).”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > Over-expression of NMNAT2 and NMNAT1 reduce neurodegeneration in rTg4510 hippocampus
What the sources say
- Supportedcites [81] Coleman, 2010, Wallerian degeneration, wld(s), and nmnat, Annu. Rev. Neurosci. source
In “The WldS Gene and Protein” (page unavailable), the review traces the protective WldS phenotype to a fusion protein identified through mouse studies. In “Defining Protective Domains in the Molecule and the Cell” (page unavailable), it states that Nmnat1 activity is essential to WldS-dependent axon protection. Together, these passages support the claim that WldS-mouse studies first implicated NMNATs in neuroprotection. (LLM, conf=0.88)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“NMNAT3-transgenic mice show delayed Wallerian degeneration similar to Wld S mice (33).”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > Over-expression of NMNAT2 and NMNAT1 reduce neurodegeneration in rTg4510 hippocampus
What the sources say
- Supportedcites [33] Yahata, 2009, Nicotinamide mononucleotide adenylyltransferase expression in mitochondrial matrix delays Wallerian degeneration, J. Neurosci. source
The Results section reports that NMNAT3-transgenic mice showed a significant delay in axonal degeneration very similar to that in WldS mice. It also reports a similar degree of axonal protection in the two groups seven days after sciatic nerve transection. (LLM, conf=0.95)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“A recent study by Hoover et al. (37) found that rTg4510 neurons have fewer NMDARs on their dendritic spines due to the mislocalization of tau protein from axons to dendritic spines.”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > Reduced CREB signaling in rTg4510 mice
What the sources say
- Supportedcites [37] Hoover, 2010, Tau mislocalization to dendritic spines mediates synaptic dysfunction independently of neurodegeneration, Neuron source
The Results (page unavailable) identify rTg4510 as rTgP301L and report decreased NR1, an NMDAR subunit, in its dendritic spines relative to controls. The Results and Discussion attribute impaired synaptic targeting or anchoring of NMDA receptors to tau mislocalization into dendritic spines. (LLM, conf=0.92)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“This differential subcellular distribution is consistent with previous observations that found NMNAT1 in the nucleus, NMNAT2 in the Golgi complex and neurites and NMNAT3 in the mitochondria (25,26,55,56).”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > Exogenous expression of NMNAT1 or NMNAT2, but not NMNAT3, provides neuroprotection in rTg4510 hippocampi
What the sources say
- Not checked — no full text of the sourcecites [25] Raffaelli, 2002, Identification of a novel human nicotinamide mononucleotide adenylyltransferase, Biochem. Biophys. Res. Commun. source
- Partly supportedcites [26] Zhang, 2003, Structural characterization of a human cytosolic NMN/NaMN adenylyltransferase and implication in human NAD biosynthesis, J. Biol. Chem. sourceExperimental — accuracy not yet measured
In Results and Discussion (page not supplied), the paper reports nuclear hsPNAT-1 and mitochondrial hsPNAT-3. It does not place hsPNAT-2 in the Golgi complex or neurites; it says its exact cellular location remains to be determined. (LLM, conf=0.91)
- Not checked — no full text of the sourcecites [55] Berger, 2005, Subcellular compartmentation and differential catalytic properties of the three human nicotinamide mononucleotide adenylyltransferase isoforms, J. Biol. Chem. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Together with the broad protective effects of NMNAT found in Drosophila (21,23,88), it has been proposed that Wld S or NMNATs protect neurons at a step common to many degenerative processes.”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > Over-expression of NMNAT2 and NMNAT1 reduce neurodegeneration in rTg4510 hippocampus
What the sources say
- Supportedcites [21] Zhai, 2008, NAD synthase NMNAT acts as a chaperone to protect against neurodegeneration, Nature source
The Abstract reports protection by NMNAT against several forms of neurodegeneration and suggests a general neuroprotective function. It also says the findings offer clues to common mechanisms underlying different neurodegenerative conditions, supporting the citing sentence’s tentative proposal. (LLM, conf=0.88)
- Supportedcites [23] Zhai, 2006, Drosophila NMNAT maintains neural integrity independent of its NAD synthesis activity, PLoS Biol. source
The Discussion (page not provided) proposes that proteasome degradation and chaperone-mediated protein folding may be involved in several neurodegenerative diseases, and links WldS to a proteasomal chaperone. Together with its findings that NMNAT protects against activity-induced degeneration, this supports the citing sentence’s hedged proposal of protection at a step shared by multiple degenerative processes. (LLM, conf=0.84)
- Partly supportedcites [88] MacDonald, 2006, The Drosophila cell corpse engulfment receptor Draper mediates glial clearance of severed axons, Neuron sourceExperimental — accuracy not yet measured
The Results report that dNmnat protects severed Drosophila axons from Wallerian degeneration, and the Discussion identifies Nmnat activity as part of WldS neuroprotection. The paper does not propose that WldS or NMNATs act at a step common to many different degenerative processes; its findings here concern injury-induced axon degeneration. Page numbers are unavailable in our copy. (LLM, conf=0.84)
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The ratios of pCREB (Ser133) to CREB in the cortex or hippocampus of rTg4510 mice were ,50% of control values, while no difference was found in the cerebellum (Fig. 2B).”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > CREB activity is reduced in rTg4510 forebrains before the onset of cognitive dysfunction
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The initial reduction in nmnat2 expression coincided with peak tau P301L expression and remained low throughout the life.”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > DISCUSSION
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Clearly, the rAAVs generated here support efficient and longlasting expression of NMNAT and EGFP in neurons located near the injection site.”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > Exogenous expression of NMNAT1 or NMNAT2, but not NMNAT3, provides neuroprotection in rTg4510 hippocampi
boosteddirectSingle case- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Analysis in 293T cells also found pCREB binding to these regions and an increase in the amount of pCREB bound to the specific CRE-containing regions upon forskolin treatment (Fig. 3B).”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > nmnat2 transcription is regulated in a CREB-dependent manner
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“However, in mice with NMNAT3 over-expression, the widths of the stratum radiatum and stratum pyramidale were similar to the EGFP expressing side (stratum radiatum, 89 + 8%, P ¼ 0.657; stratum pyramidale, 98 + 12%, P ¼ 0.883).”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > Exogenous expression of NMNAT1 or NMNAT2, but not NMNAT3, provides neuroprotection in rTg4510 hippocampi
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Furthermore, our luciferase studies indicated that both the CREs are required for nmnat2 transcription as mutating either one abolishes transcription of nmnat2, suggesting transcriptional regulation in a cooperative manner.”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > nmnat2 transcription is regulated in a CREB-dependent manner
hedgeddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“EGFP was expressed at high levels in dendrites, and transgene expression had no detectable impact on the hippocampal structure (Fig. 6A).”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > Exogenous expression of NMNAT1 or NMNAT2, but not NMNAT3, provides neuroprotection in rTg4510 hippocampi
plainSingle case- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Interestingly, we also observed reduced levels of activated cleaved caspase 3 (Fig. 7A and D; ratios of activated cleaved caspase 3 to un-cleaved caspase 3: ctrl, 100 + 26%; NMNAT2, 17 + 12%; P ¼ 0.01) and GFAP (Fig. 7A and E; ctrl, 100 + 10%; NMNAT2, 65 + 13%; P , 0.05) in the NMNAT2-injected rTg4510 hippocampi compared with the EGFP injected rTg4510 hippocampi.”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > Exogenous expression of NMNAT1 or NMNAT2, but not NMNAT3, provides neuroprotection in rTg4510 hippocampi
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Dual EGFP (green) and NMNAT1 (N1, red) immunostaining shows strong ectopic expression of EGFP or NMNAT1 at 5 months of age (C).”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > Chromatin immunoprecipitation (ChIP) analysis
boosted- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We found that pCREB occupancy was significantly reduced at both the promoter with CRE1 + CRE2 and the one with CRE2 alone in the rTg4510 cortex (P , 0.05 for CRE1 + CRE2; P , 0.001 for CRE2) and hippocampus (P , 0.001 for CRE1 + CRE2 and P , 0.05 for CRE2) (Fig. 4; Supplementary Ma- terial, Table S3).”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > nmnat2 transcription is regulated in a CREB-dependent manner
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“As expected, NMNAT1 immunoreactivity was found in the nucleus (Fig. 5E), while NMNAT2 immunoreactivity was found in neurites (Fig. 5F), but not in the nucleus.NMNAT3 was mainly found in the cytoplasm (Fig. 5G).”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > Exogenous expression of NMNAT1 or NMNAT2, but not NMNAT3, provides neuroprotection in rTg4510 hippocampi
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“NMNAT3 over-expression did not have an impact on hippocampal size.”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > Chromatin immunoprecipitation (ChIP) analysis
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The quote only partly states this claim.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The distinct subcellular distribution of ectopic NMNAT1-3 expression in cultured cortical neurons.”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > Chromatin immunoprecipitation (ChIP) analysis
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Interestingly, several gene-array studies found that NMNAT2 levels were reduced in brain specimens from patients with Alzheimer's disease (AD; https://www.nextbio.com).”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > INTRODUCTION
What the sources say
- Not matchedcites https://www.nextbio.com
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Not matched
In the paper
“Tauopathies include several neurodegenerative diseases such as Pick's disease and frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17; reviewed in 1).”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > INTRODUCTION
What the sources say
- Not checked — no full text of the sourcecites [1] Lee, 2001, Neurodegenerative tauopathies, Annu. Rev. Neurosci. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, the decrease in cortical NMNAT2 coincides with tau P301L over-expression and precedes significant neuronal loss.”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > NMNAT2 is down-regulated in the rTg4510 mouse brain prior to neurodegeneration
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Immunoprecipitation was performed with the following antibodies: anti-pCREB (Ser133) (Millipore), Rabbit IgG (negative control; Millipore) or anti-RNAPolII (positive control; Millipore).”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > Chromatin immunoprecipitation (ChIP) analysis
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Only the brains with similar amounts of EGFP in the CA1 area of hippocampus in both hemispheres were chosen for further immunofluorescence analysis.”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > Tissue processing
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“A housekeeping gene, gapdh, was used as an internal control to normalize mRNA expression.”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > RNA extraction and quantitative real-time PCR
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“nmnat2 is likely to be a CREB target necessary for maintaining neuronal health at physiological conditions.”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > Reduced CREB signaling in rTg4510 mice
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“In this spontaneous mutant, the Wallerian degeneration process is significantly delayed (82).”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > Over-expression of NMNAT2 and NMNAT1 reduce neurodegeneration in rTg4510 hippocampus
What the sources say
- Not checked — no full text of the sourcecites [82] Lunn, 1989, Absence of Wallerian degeneration does not hinder regeneration in peripheral nerve, Eur. J. Neurosci. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Taken together, our studies demonstrate down-regulation of NMNAT2 and CREB activity in the central nervous system (CNS) of a tauopathy animal model.”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > DISCUSSION
boostedcorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These results suggest that overexpression of NMNAT2 protects against tau-induced degeneration by reducing the toxic hyperphosphorylated tau load and ameliorates tau-induced cytotoxicity.”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > Exogenous expression of NMNAT1 or NMNAT2, but not NMNAT3, provides neuroprotection in rTg4510 hippocampi
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: The EGFP-rAAV-injected hemisphere provides a valid internal control for the effects of NMNAT-rAAV in rTg4510 mice.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“ChIP experiments were replicated three times incorporating all the appropriate controls.”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > Chromatin immunoprecipitation (ChIP) analysis
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“Various transgenic and pharmacological approaches that augment NMDAR signaling have been found to increase learning and memory in mice, for example, NR2B overexpression and application of NMDAR partial agonist, D-cycloserine (79,80).”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > Reduced CREB signaling in rTg4510 mice
What the sources say
- Not checked — no full text of the sourcecites [79] Thompson, 1992, Hippocampus-dependent learning facilitated by a monoclonal antibody or D-cycloserine, Nature source
- Not checked — no full text of the sourcecites [80] Flood, 1992, Effect on memory processing by D-cycloserine, an agonist of the NMDA/glycine receptor, Eur. J. Pharmacol. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“CREB binds to CREs in the promoter region of their target genes (69), but will only activate gene transcription upon phosphorylation at Ser133 (40).”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > Reduced CREB signaling in rTg4510 mice
What the sources say
- Not matchedcites [69] Impey, 2004, Defining the CREB regulon: a genome-wide analysis of transcription factor regulatory regions, Cell
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not checked — no full text of the sourcecites [40] Mayr, 2001, Transcriptional regulation by the phosphorylation-dependent factor CREB, Nat. Rev. Mol. Cell Biol. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Not matched
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The extensive EGFP-positive area in the CA1 region indicates successful rAAV injections.”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > Chromatin immunoprecipitation (ChIP) analysis
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
The paper relies on this without support.
The precise mechanism of cell death in tauopathies remains unknown.
“Although there is evidence for the presence of activated caspase and morphological features of necrosis, autophagy and abnormal cell cycle events (10,13,15 -18), the precise mechanism of cell death in tauopathies remains unknown.”
The paper relies on this without support.
The EGFP-rAAV-injected hemisphere provides a valid internal control for the effects of NMNAT-rAAV in rTg4510 mice.
“NMNAT1-, NMNAT2-or NMNAT3-rAAV was injected into the CA1/ Thicknesses were analyzed by taking six measurements per section and three sections per animal.The three 50 mm sections were separated by dentate gyrus area of the hippocampus in the right hemisphere, while EGFP-rAAV was injected into the left hemisphere as an internal control.”
The paper relies on this without support.
The reduction in NMNAT2 protein levels in rTg4510 mice is primarily due to reduced nmnat2 transcription rather than altered protein stability.
“Thus, the decrease in the NMNAT2 protein in rTg4510 mice was accompanied by a down-regulation of nmnat2 transcripts in the cortex at 1 month of age and older, and in the hippocampus at 2 months of age and older.”
The paper relies on this without support.
The thickness of the stratum radiatum and stratum pyramidale reflects hippocampal neuronal loss in rTg4510 mice.
“To quantify the impact of NMNAT over-expression on CA1 structures, we measured the thickness of the stratum radiatum and the stratum pyramidale guided by synapsin immunoreactivity and DAPI staining (see Materials and Methods).”
The paper relies on this without support.
NMDAR-dependent long-term potentiation is impaired in the Schaffer collateral pathway of rTg4510 mice at 4.5 months of age.
“NMDAR-dependent long-term potentiation was impaired in the Schaffer collateral pathway of rTg4510 mice at 4.5 months of age.”
The paper relies on this without support.
Over-expression of NMNAT substantially reduces the formation of protein aggregates such as hAtx-1[82Q] protein in Drosophila.
“Over-expression of NMNAT substantially reduced the formation of protein aggregates such as hAtx-1[82Q] protein, the cause of spinocerebellar ataxia 1, in Drosophila.”
The paper relies on this without support.
Synapsin immunoreactivity is a valid estimate of neuronal morphology and anatomical integrity in rTg4510 mice.
“In this study, we used the immunoreactivity of synapsin, a synaptic marker, to estimate neuronal morphology and anatomical integrity in rTg4510 mice.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“To control false discovery rate, Benjamini-Hochberg procedure was applied with a false discovery rate of 0.1 35, 36”
From Amyloid-beta induced retrograde axonal degeneration in a mouse tauopathy model (2019) · cites this paper as [36]
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Rated major: it would touch a result — a value a result rests on, reported and recomputed p-values on opposite sides of the significance level, two passages that conflict with no sign which is right, or a cited work retracted before this paper was published.
In the paper
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > Tissue processing
“Mice (control and rTg4510) used for real-time qPCR and protein analysis were sacrificed at 2 weeks, 1 month and 2 months of age (n ¼ 3 per genotype and age).”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > Chromatin immunoprecipitation (ChIP) analysis
“Western data are presented as percentages of their age-matched controls and are plotted as mean + SEM (for 1-month-old, n ¼ 10 for each genotype; for other age groups, n ¼ 3 for each genotype group).”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > Exogenous expression of NMNAT1 or NMNAT2, but not NMNAT3, provides neuroprotection in rTg4510 hippocampi
“cultured cortical neurons derived from ICR mice were transduced with rAAV at 2 days in vitro (DIV) and NMNAT expression was examined at six DIV.”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > Chromatin immunoprecipitation (ChIP) analysis
“Cortical neurons were infected by rAAVs at 2 DIV and stained with EGFP and NMNAT1, NMNAT2 or NMNAT3 antibodies at 8 DIV.”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > Tissue processing
“Mice (control and rTg4510) used for real-time qPCR and protein analysis were sacrificed at 2 weeks, 1 month and 2 months of age (n ¼ 3 per genotype and age).”
§ CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy > NMNAT2 is down-regulated in the rTg4510 mouse brain prior to neurodegeneration
“Specific brain areas, including the cortex, hippocampus and cerebellum from rTg4510 mice and their littermate controls at 2 weeks, 1, 2 and 7 months of age were analyzed (n ¼ 3 for each age group and each genotype).”
Citations
Cites
Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2−ΔΔCT Method
Livak, K. J., & Schmittgen, T. D. (2001) · Methods · doi:10.1006/meth.2001.1262 · Cited by 180,860
Triple-Transgenic Model of Alzheimer’s Disease with Plaques and Tangles
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Association of missense and 5′-splice-site mutations in tau with the inherited dementia FTDP-17
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Transcriptional regulation by the phosphorylation-dependent factor CREB
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Synapse Loss and Microglial Activation Precede Tangles in a P301S Tauopathy Mouse Model
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Function and regulation of CREB family transcription factors in the nervous system
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Tau Suppression in a Neurodegenerative Mouse Model Improves Memory Function
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“To test for potential pCREB binding to the putative CREs, we performed chromatin immunoprecipitation (ChIP) experiments with a pCREB (Ser133) antibody, using both mouse whole-brain extract and extracts from 293T cells treated with either dimethyl sulfoxide (DMSO) or 10 mM forskolin, an activator of adenylyl cyclases (…”
Method
Cited by
Sorted by citations
Wallerian degeneration: an emerging axon death pathway linking injury and disease
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The Organic Anion Transporter (OAT) Family: A Systems Biology Perspective
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Role of NAD+ in regulating cellular and metabolic signaling pathways
Amjad, S., Nisar, S., Bhat, A. A., Shah, A. R., Frenneaux, M. P., Fakhro, K. A., Haris, M., Reddy, R. D., Patay, Z. J., Baur, J. A., et al. (2021) · Molecular Metabolism · doi:10.1016/j.molmet.2021.101195 · Cited by 413
Mechanisms of α-Synuclein Induced Synaptopathy in Parkinson's Disease
Bridi, J. C., & Hirth, F. (2018) · Frontiers in Neuroscience · doi:10.3389/fnins.2018.00080 · Cited by 396
“NMNAT2 alterations were also found in a mouse model of tauopathy expressing mis-sense mutation P301L, found in some frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) cases (Ljungberg et al., 2012).”
BackgroundProgrammed axon degeneration: from mouse to mechanism to medicine
Coleman, M. P., & Höke, A. (2020) · Nature reviews. Neuroscience · doi:10.1038/s41583-020-0269-3 · Cited by 329
Metadata
- Authors
- Ljungberg, M. C., Ali, Y. O., Zhu, J., Wu, C.-S., Oka, K., Zhai, R. G., & Lu, H.-C.
- Affiliations
- Baylor College of Medicine (US)
- University of Miami (US)
- Neurological Research Institute (US)
- Corresponding author
- Lu, Hui-Chen
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2011-10-25
- Volume
- 21
- Issue
- 2
- Pages
- 251-267
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- PMC
- PMC3276285
- OpenAlex
- W2127395697
- Cited by
- 107
- References
- 101
- Citations by year
- 2026: 5 · 2025: 4 · 2024: 3 · 2023: 4 · 2022: 9 · 2021: 9 · 2020: 6 · 2019: 13 · 2018: 12 · 2017: 11 · 2016: 6 · 2015: 1 · 2014: 8 · 2013: 11 · 2012: 5
- FWCI
- 5.22
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Heart Association
- National Heart, Lung, and Blood Institute (HL73144, R01HL073144)
- National Institute on Drug Abuse (R21DA029381, DA029381)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK-79638, P30DK079638)
- National Institute of Neurological Disorders and Stroke (R01NS048884, R01NS064269, R56NS064269, NS048884, NS64269)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD065561, R21HD065561)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Clinical Neurology › Amyotrophic Lateral Sclerosis Research
- Keywords
- tauopathy, NMNAT2, CREB, cAMP response element, P301L tau, rTg4510 mice, neurodegeneration, neuroprotection, neurofibrillary tangles, frontotemporal dementia, Alzheimer's disease, hippocampus, adeno-associated virus vectors, neuronal survival
- MeSH terms
- Animals, Base Sequence, Disease Models, Animal, Fluorescent Antibody Technique, Hippocampus, Humans, Mice, Transgenic, Nicotinamide-Nucleotide Adenylyltransferase, Promoter Regions, Genetic, Transcription, Genetic, Blotting, Western, Down-Regulation, DNA Primers, Tauopathies, CREB-Binding Protein, Mice, Real-Time Polymerase Chain Reaction
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-10-30, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-30 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Cited sources are checked with a language model’s help (gpt-6-sol).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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