CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy

In the paper

“Substantial neurodegeneration is observed after 5 months of age, being most apparent in the hippocampal CA1 area (14,34,35).”

What the sources say

• Partly supported

  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)

  cites [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
• Supported

  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)

  cites [34] Ramsden, 2005, Age-dependent neurofibrillary tangle formation, neuron loss, and memory impairment in a mouse model of human tauopathy (P301L), J. Neurosci. source
• ?Not checked — no full text of the sourcecites [35] Santacruz, 2005, Tau suppression in a neurodegenerative mouse model improves memory function, Science source

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).”

What the sources say

• Supported

  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)

  cites [24] Emanuelli, 2001, Molecular cloning, chromosomal localization, tissue mRNA levels, bacterial expression, and enzymatic properties of human NMN adenylyltransferase, J. Biol. Chem. source
• ?Not checked — no full text of the sourcecites [25] Raffaelli, 2002, Identification of a novel human nicotinamide mononucleotide adenylyltransferase, Biochem. Biophys. Res. Commun. source
• Supported

  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)

  cites [26] Zhang, 2003, Structural characterization of a human cytosolic NMN/NaMN adenylyltransferase and implication in human NAD biosynthesis, J. Biol. Chem. source
• Supported

  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)

  cites [27] Gilley, 2010, Endogenous Nmnat2 is an essential survival factor for maintenance of healthy axons, PLoS Biol. source

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).”

What the sources say

• Partly supported

  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)

  cites [8] Gotz, 2001, Tau filament formation in transgenic mice expressing P301L tau, J. Biol. Chem. sourceExperimental — accuracy not yet measured
• ?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 supported

  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)

  cites [11] Yoshiyama, 2007, Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model, Neuron sourceExperimental — accuracy not yet measured

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.”

What the sources say

• Supported

  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)

  cites [34] Ramsden, 2005, Age-dependent neurofibrillary tangle formation, neuron loss, and memory impairment in a mouse model of human tauopathy (P301L), J. Neurosci. source
• ?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

In the paper

“However, neuronal loss appears to be independent of tangle formation in some transgenic mouse models (12)(13)(14).”

What the sources say

• ?Not checked — no full text of the sourcecites [12] Wittmann, 2001, Tauopathy in Drosophila: neurodegeneration without neurofibrillary tangles, Science source
• Supported

  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)

  cites [13] Andorfer, 2005, Cell-cycle reentry and cell death in transgenic mice expressing nonmutant human tau isoforms, J. Neurosci. source
• Supported

  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)

  cites [14] Spires, 2006, Region-specific dissociation of neuronal loss and neurofibrillary pathology in a mouse model of tauopathy, Am. J. Pathol. source

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).”

What the sources say

• Supported

  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)

  cites [27] Gilley, 2010, Endogenous Nmnat2 is an essential survival factor for maintenance of healthy axons, PLoS Biol. source

In the paper

“Mutant tau expression starts around postnatal day 7 and peaks at 1 month of age (34,35).”

What the sources say

• Partly supported

  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)

  cites [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
• ?Not checked — no full text of the sourcecites [35] Santacruz, 2005, Tau suppression in a neurodegenerative mouse model improves memory function, Science source

In the paper

“Several tau mutations linked to FTDP-17 have been identified (2 -7)”

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
• Supported

  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)

  cites [7] Goedert, 2005, Mutations causing neurodegenerative tauopathies, Biochim. Biophys. Acta source

In the paper

“Over-expression of NMNAT, on the other hand, provides neuroprotection against several degenerative conditions in Drosophila (21,23).”

What the sources say

• Supported

  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)

  cites [21] Zhai, 2008, NAD synthase NMNAT acts as a chaperone to protect against neurodegeneration, Nature source
• Supported

  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)

  cites [23] Zhai, 2006, Drosophila NMNAT maintains neural integrity independent of its NAD synthesis activity, PLoS Biol. source

In the paper

“Loss of nmnat in the Drosophila eye causes rapid neuronal degeneration (23).”

What the sources say

• Supported

  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)

  cites [23] Zhai, 2006, Drosophila NMNAT maintains neural integrity independent of its NAD synthesis activity, PLoS Biol. source

In the paper

“In mammals, over-expressing NMNATs significantly delays Wallerian degeneration of peripheral nerves (28)(29)(30)(31)(32)(33).”

What the sources say

• Partly supported

  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)

  cites [28] Press, 2008, Nmnat delays axonal degeneration caused by mitochondrial and oxidative stress, J. Neurosci. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [29] Araki, 2004, Increased nuclear NAD biosynthesis and SIRT1 activation prevent axonal degeneration, Science source
• Partly supported

  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)

  cites [30] Wang, 2005, A local mechanism mediates NAD-dependent protection of axon degeneration, J. Cell Biol. sourceExperimental — accuracy not yet measured
• Partly supported

  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)

  cites [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
• Supported

  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)

  cites [32] Sasaki, 2009, Transgenic mice expressing the Nmnat1 protein manifest robust delay in axonal degeneration in vivo, J. Neurosci. source
• Partly supported

  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)

  cites [33] Yahata, 2009, Nicotinamide mononucleotide adenylyltransferase expression in mitochondrial matrix delays Wallerian degeneration, J. Neurosci. sourceExperimental — accuracy not yet measured

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).”

What the sources say

• Supported

  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)

  cites [37] Hoover, 2010, Tau mislocalization to dendritic spines mediates synaptic dysfunction independently of neurodegeneration, Neuron source

In the paper

“NAD + is used to synthesize NADP + , whose reduced form NADPH is involved in defense against oxidative stress (91).”

What the sources say

• Supported

  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)

  cites [91] Pollak, 2007, The power to reduce: pyridine nucleotides—small molecules with a multitude of functions, Biochem. J. source

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).”

What the sources say

• Partly supported

  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)

  cites [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
• ?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

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).”

What the sources say

• Supported

  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)

  cites [81] Coleman, 2010, Wallerian degeneration, wld(s), and nmnat, Annu. Rev. Neurosci. source
• Supported

  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)

  cites [89] Zhai, 2009, Nicotinamide/nicotinic acid mononucleotide adenylyltransferase, new insights into an ancient enzyme, Cell Mol. Life Sci. source

In the paper

“Ab oligomers also cause tau mislocalization (77,78).”

What the sources say

• ?Could not verify

  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)

  cites [77] Ittner, 2010, Dendritic function of tau mediates amyloid-beta toxicity in Alzheimer's disease mouse models, Cell sourceExperimental — accuracy not yet measured
• Supported

  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)

  cites [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

In the paper

“NMDAR (N-methyl-D-aspartate receptors)-mediated calcium influx is known to increase pCREB levels through several signaling pathways (65).”

What the sources say

• Supported

  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)

  cites [65] Lonze, 2002, Function and regulation of CREB family transcription factors in the nervous system, Neuron source

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).”

What the sources say

• Supported

  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)

  cites [38] Lee, 2009, The molecular and cellular biology of enhanced cognition, Nat. Rev. Neurosci. source

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).”

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 supported

  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)

  cites [68] Valor, 2010, Ultrastructural and transcriptional profiling of neuropathological misregulation of CREB function, Cell Death Differ. sourceExperimental — accuracy not yet measured

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).”

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
• Supported

  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)

  cites [86] Sajadi, 2004, Wlds-mediated protection of dopaminergic fibers in an animal model of Parkinson disease, Curr. Biol. source
• ?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

In the paper

“CREB is also important for cell survival (65,66).”

What the sources say

• Supported

  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)

  cites [65] Lonze, 2002, Function and regulation of CREB family transcription factors in the nervous system, Neuron source
• ?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

In the paper

“Interestingly, NMNAT over-expression can prevent axonal damage resulting from exogenous application of oxidants (28).”

What the sources say

• Supported

  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)

  cites [28] Press, 2008, Nmnat delays axonal degeneration caused by mitochondrial and oxidative stress, J. Neurosci. source

In the paper

“The role of NMNATs in neuroprotection was first implicated in studies using Wallerian Slow mice (Wld S ; reviewed in 81).”

What the sources say

• Supported

  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)

  cites [81] Coleman, 2010, Wallerian degeneration, wld(s), and nmnat, Annu. Rev. Neurosci. source

In the paper

“NMNAT3-transgenic mice show delayed Wallerian degeneration similar to Wld S mice (33).”

What the sources say

• Supported

  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)

  cites [33] Yahata, 2009, Nicotinamide mononucleotide adenylyltransferase expression in mitochondrial matrix delays Wallerian degeneration, J. Neurosci. source

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.”

What the sources say

• Supported

  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)

  cites [37] Hoover, 2010, Tau mislocalization to dendritic spines mediates synaptic dysfunction independently of neurodegeneration, Neuron source

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).”

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 supported

  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)

  cites [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
• ?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

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.”

What the sources say

• Supported

  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)

  cites [21] Zhai, 2008, NAD synthase NMNAT acts as a chaperone to protect against neurodegeneration, Nature source
• Supported

  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)

  cites [23] Zhai, 2006, Drosophila NMNAT maintains neural integrity independent of its NAD synthesis activity, PLoS Biol. source
• Partly supported

  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)

  cites [88] MacDonald, 2006, The Drosophila cell corpse engulfment receptor Draper mediates glial clearance of severed axons, Neuron sourceExperimental — accuracy not yet measured

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).”

In the paper

“The initial reduction in nmnat2 expression coincided with peak tau P301L expression and remained low throughout the life.”

In the paper

“Clearly, the rAAVs generated here support efficient and longlasting expression of NMNAT and EGFP in neurons located near the injection site.”

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).”

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).”

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.”

In the paper

“EGFP was expressed at high levels in dendrites, and transgene expression had no detectable impact on the hippocampal structure (Fig. 6A).”

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.”

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).”

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).”

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).”

In the paper

“NMNAT3 over-expression did not have an impact on hippocampal size.”

In the paper

“The distinct subcellular distribution of ectopic NMNAT1-3 expression in cultured cortical neurons.”

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).”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites https://www.nextbio.com

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).”

What the sources say

• ?Not checked — no full text of the sourcecites [1] Lee, 2001, Neurodegenerative tauopathies, Annu. Rev. Neurosci. source

In the paper

“Thus, the decrease in cortical NMNAT2 coincides with tau P301L over-expression and precedes significant neuronal loss.”

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).”

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.”

In the paper

“A housekeeping gene, gapdh, was used as an internal control to normalize mRNA expression.”

In the paper

“nmnat2 is likely to be a CREB target necessary for maintaining neuronal health at physiological conditions.”

In the paper

“In this spontaneous mutant, the Wallerian degeneration process is significantly delayed (82).”

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

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.”

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.”

In the paper

“ChIP experiments were replicated three times incorporating all the appropriate controls.”

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).”

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

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).”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites [69] Impey, 2004, Defining the CREB regulon: a genome-wide analysis of transcription factor regulatory regions, Cell
• ?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

In the paper

“The extensive EGFP-positive area in the CA1 region indicates successful rAAV injections.”