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Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice
Open accessAbstract
β-Site APP-cleaving enzyme 1 (BACE1) initiates amyloid-β (Aβ) generation and thus represents a prime therapeutic target in treating Alzheimer's disease (AD). Notably, increasing evidence indicates that BACE1 levels become elevated in AD brains as disease progresses; however, it remains unclear how the BACE1 upregulation may affect efficacies of therapeutic interventions including BACE1-inhibiting approaches. Here, we crossed heterozygous BACE1 knockout mice with AD transgenic mice (5XFAD model) and compared the abilities of partial BACE1 reduction to rescue AD-like phenotypes at earlier (6-month-old) and advanced (15-18-month-old) stages of disease, which expressed normal (∼100%) and elevated (∼200%) levels of BACE1, respectively. BACE1(+/-) deletion rescued memory deficits as tested by the spontaneous alternation Y-maze task in 5XFAD mice at the earlier stage and prevented their septohippocampal cholinergic deficits associated with significant neuronal loss. Importantly, BACE1(+/-) deletion was no longer able to rescue memory deficits or cholinergic neurodegeneration in 5XFAD mice at the advanced stage. Moreover, BACE1(+/-) deletion significantly reduced levels of Aβ42 and the β-secretase-cleaved C-terminal fragment (C99) in 6-month-old 5XFAD mouse brains, while these neurotoxic β-cleavage products dramatically elevated with age and were not affected by BACE1(+/-) deletion in 15-18-month-old 5XFAD brains. Interestingly, although BACE1(+/-) deletion lowered BACE1 expression by ∼50% in 5XFAD mice irrespective of age in concordance with the reduction in gene copy number, BACE1 equivalent to wild-type controls remained in BACE1(+/-)·5XFAD mice at the advanced age. In accord, phosphorylation of the translation initiation factor eIF2α, an important mediator of BACE1 elevation, was dramatically increased (∼9-fold) in 15-18-month-old 5XFAD mice and remained highly upregulated (∼6-fold) in age-matched BACE1(+/-)·5XFAD mice. Together, our results indicate that partial reduction of BACE1 is not sufficient to block the phospho-eIF2α-dependent BACE1 elevation during the progression of AD, thus limiting its abilities to reduce cerebral Aβ/C99 levels and rescue memory deficits and cholinergic neurodegeneration.
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TL;DR
Partial (heterozygous) BACE1 reduction rescued memory deficits and septohippocampal cholinergic neurodegeneration in 6-month-old 5XFAD mice but failed to do so at 15–18 months, when BACE1 and phospho-eIF2α were elevated. The results suggest that phospho-eIF2α-driven BACE1 elevation limits the efficacy of partial BACE1 suppression as Alzheimer’s-like disease progresses.
Key findings
- BACE1+/− deletion rescued spontaneous alternation Y-maze deficits in 6-month-old 5XFAD mice, but not in 15–18-month-old 5XFAD mice (no significant difference between 5XFAD and BACE1+/−·5XFAD, p = 0.24).
- BACE1+/− deletion restored hippocampal ChAT levels and ChAT-positive Ch1/2 neuron numbers in 6-month-old 5XFAD mice, but not at 15–18 months (ChAT trend p = 0.10; neuron number p = 0.32).
- BACE1+/− deletion reduced C99 by ∼53% and Aβ42 by ∼67% in 6-month-old 5XFAD brains; at 15–18 months, reductions were only ∼18% for C99 and ∼20% for Aβ42 and not significant (p = 0.14 and p = 0.19).
- BACE1 levels were ∼200% of wild-type in 15–18-month-old 5XFAD mice; BACE1+/− reduced BACE1 by ∼50% but residual BACE1 remained equivalent to wild-type. Phospho-eIF2α was ∼9-fold elevated in old 5XFAD and remained ∼6-fold elevated in BACE1+/−·5XFAD; Sal 003-induced phospho-eIF2α elevation increased BACE1 in 6-month-old 5XFAD slices.
Methods
- Crossbred heterozygous BACE1 knockout mice with 5XFAD transgenic mice to generate wild-type, BACE1+/−, 5XFAD, and BACE1+/−·5XFAD genotypes; tested at 6 months and 15–18 months of age.
- Behavioral testing used the spontaneous alternation Y-maze; biochemical measures included immunoblot for BACE1, APP, C99, phospho-eIF2α, ChAT, and β-actin; ChAT immunohistochemistry in medial septum/vertical limb of diagonal band; and Aβ42 sandwich ELISA.
- Brain slices from 6-month-old 5XFAD mice were treated with Sal 003 (30 µM) to inhibit phospho-eIF2α phosphatase; statistical analysis used one-way ANOVA with post-hoc Fisher’s PLSD, p < 0.05.
Limitations
- The paper does not state a dedicated limitations section.
- Evident from the text: findings are restricted to the 5XFAD mouse model and two age points (6 months and 15–18 months), with small group sizes (n = 4–12 per group in reported experiments).
- Evident from the text: BACE1 reduction was achieved by heterozygous genetic deletion, not pharmacological BACE1 inhibition, so direct clinical dosing implications remain untested.
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In the paper
“ChAT levels in the hippocampus of both 5XFAD and BACE1+/−·5XFAD mice at 15–18 months of age were significantly lower than those of wild-type control mice (F (2,24) = 10.51, p<0.05)”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Results > Abilities of partial BACE1 reduction to rescue cholinergic neurodegeneration decline with age in 5XFAD mice
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“Aβ42 levels were not significantly different between BACE1+/−·5XFAD and 5XFAD mice at 15–18 months of age (F (1,6) = 2.23, p = 0.19).”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Results > Age-related effects of partial BACE1 reduction on APP processing and Aβ levels in 5XFAD mice
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In the paper
“BACE1+/− ablation significantly lowered excessive levels of Aβ42 in 6-month-old 5XFAD mouse brains (F (1,6) = 23.53, p<0.05).”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Results > Age-related effects of partial BACE1 reduction on APP processing and Aβ levels in 5XFAD mice
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In the paper
“Levels of the β-secretase-cleaved C-terminal fragment (C99) were significantly reduced in BACE1+/−·5XFAD mice at 6 months of age as compared to 5XFAD mice (F (1,10) = 7.37, p<0.05)”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Results > Age-related effects of partial BACE1 reduction on APP processing and Aβ levels in 5XFAD mice
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In the paper
“Post-hoc Fisher's PLSD test indicated only a trend toward slight increases in ChAT levels of BACE1+/−·5XFAD mice compared to those of 5XFAD littermates (p = 0.10).”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Results > Abilities of partial BACE1 reduction to rescue cholinergic neurodegeneration decline with age in 5XFAD mice
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“while it was no longer able to significantly influence levels of these β-products in 15–18-month-old 5XFAD mouse brains (∼18% and ∼20% reductions, respectively).”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Results > Age-related effects of partial BACE1 reduction on APP processing and Aβ levels in 5XFAD mice
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In the paper
“the spatial working memory deficits were rescued to wild-type levels in 5XFAD mice with BACE1+/− genotype, which exhibited significantly higher spontaneous alternation than did 5XFAD mice (p<0.05)”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Results > Abilities of partial BACE1 reduction to rescue memory dysfunction decline with age in 5XFAD mice
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“the residual levels of BACE1 in older BACE1+/−·5XFAD mouse brains were equivalent to those of wild-type controls.”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Results > Age-related effects of partial BACE1 reduction on BACE1 and phospho-eIF2α levels in 5XFAD mice
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In the paper
“the elevated levels of C99 were no longer significantly affected by BACE1+/− deletion at this advanced age (F (1,9) = 2.57, p = 0.14).”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Results > Age-related effects of partial BACE1 reduction on APP processing and Aβ levels in 5XFAD mice
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“C99 levels in 15–18-month-old 5XFAD mouse brains were significantly higher than those of 6-month-old 5XFAD brains (∼172%) (F (1,10) = 10.71, p<0.05)”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Results > Age-related effects of partial BACE1 reduction on APP processing and Aβ levels in 5XFAD mice
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“At 6 months of age, the 5XFAD-associated increase in phospho-eIF2α level was marginal and it was completely abolished in BACE1+/−·5XFAD mice (F (2,11) = 25.76, p<0.05)”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Results > Age-related effects of partial BACE1 reduction on BACE1 and phospho-eIF2α levels in 5XFAD mice
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“Post-hoc Fisher's PLSD test revealed no significant difference in alternation performances between 5XFAD and BACE1+/−·5XFAD mice (p = 0.24), indicating that BACE1+/− deletion failed to improve the spatial working memory defect in 5XFAD mice at this advanced age.”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Results > Abilities of partial BACE1 reduction to rescue memory dysfunction decline with age in 5XFAD mice
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“the number of ChAT-immunoreactive neurons in 5XFAD and BACE1+/−·5XFAD mice at 15–18 months of age was significantly lower than that of wild-type control mice (F (2,13) = 8.49, p<0.05) and was indistinguishable from each other according to post-hoc Fisher's PLSD test (p = 0.32).”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Results > Abilities of partial BACE1 reduction to rescue cholinergic neurodegeneration decline with age in 5XFAD mice
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In the paper
“BACE1+/− deletion significantly suppressed the β-cleavage of APP in 5XFAD mice at 6 months of age resulting in reduced levels of C99 and Aβ42 (by ∼53% and ∼67%, respectively)”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Results > Age-related effects of partial BACE1 reduction on APP processing and Aβ levels in 5XFAD mice
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In the paper
“Importantly, we found that BACE1+/− deletion restored the cholinergic defects to normal consistent with improvements in hippocampal spatial memory function in 5XFAD mice at 6 months of age.”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Discussion
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In the paper
“Although heterozygous knockout also reduced BACE1 expression by ∼50% in 15–18-month-old 5XFAD mice in concordance with the reduction in gene copy number, their C99 levels were not significantly lower than age-matched 5XFAD levels.”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Discussion
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In the paper
“5XFAD mice begin to develop visible amyloid deposition as early as 2 months of age and exhibit memory declines on hippocampus-dependent tasks between 4–6 months with moderate Aβ accumulation [8], [28], [29], [30], [31].”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Introduction
What the sources say
- Not checked yetcites [8] Ohno M Chang L Tseng W Oakley H Citron M 2006 Temporal memory deficits in Alzheimer's mouse models: rescue by genetic deletion of BACE1. Eur J Neurosci 23 251 260 16420434
- Not checked yetcites [28] Oakley H Cole SL Logan S Maus E Shao P 2006 Intraneuronal β-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer's disease mutations: potential factors in amyloid plaque formation. J Neurosci 26 10129 10140 17021169 PMC6674618
- Not checked yetcites [29] Kimura R Ohno M 2009 Impairments in remote memory stabilization precede hippocampal synaptic and cognitive failures in 5XFAD Alzheimer mouse model. Neurobiol Dis 33 229 235 19026746 PMC2741400
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“the β-secretase (BACE1: β-site amyloid precursor protein cleaving enzyme 1), which is responsible for initiating the production of Aβ, represents an excellent therapeutic target for the treatment of AD [3], [4], [5], [6].”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Introduction
What the sources say
- Not checked yetcites [3] Citron M 2004 β-Secretase inhibition for the treatment of Alzheimer's disease–promise and challenge. Trends Pharmacol Sci 25 92 97 15102495
- Not checked yetcites [4] Ohno M 2006 Genetic and pharmacological basis for therapeutic inhibition of β- and γ-secretases in mouse models of Alzheimer's memory deficits. Rev Neurosci 17 429 454 17139843
- Not checked yetcites [5] Ohno M 2008 β-Secretase as a prime therapeutic target for Alzheimer's disease: a perspective from mouse model studies. Araki W Recent Advances in the Biology of Secretases, Key Proteases in Alzheimer's Disease Kerala Research Signpost 1 25
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Probably not a substantial claim. It may be too vague to check against evidence.
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In the paper
“partial reduction of BACE1 suffices to attenuate Aβ-related pathology and rescue synaptic and memory deficits in mouse models of AD [18], [19], [20], [21], [22].”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Introduction
What the sources say
- Not checked yetcites [18] Singer O Marr RA Rockenstein E Crews L Coufal NG 2005 Targeting BACE1 with siRNAs ameliorates Alzheimer disease neuropathology in a transgenic model. Nat Neurosci 8 1343 1349 16136043
- Not checked yetcites [19] Chang WP Downs D Huang XP Da H Fung KM 2007 Amyloid-β reduction by memapsin 2 (β-secretase) immunization. FASEB J 21 3184 3196 17494994
- Not checked yetcites [20] McConlogue L Buttini M Anderson JP Brigham EF Chen KS 2007 Partial reduction of BACE1 has dramatic effects on Alzheimer plaque and synaptic pathology in APP transgenic mice. J Biol Chem 282 26326 26334 17616527
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In the paper
“evidence is accumulating that BACE1 expression and activity levels are significantly elevated in sporadic AD brains, which is considered a crucial contributing factor in the pathogenesis of this enigmatic disease [23], [24], [25], [26], [27].”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Introduction
What the sources say
- Not checked yetcites [23] Fukumoto H Cheung BS Hyman BT Irizarry MC 2002 β-Secretase protein and activity are increased in the neocortex in Alzheimer disease. Arch Neurol 59 1381 1389 12223024
- Not checked yetcites [24] Li R Lindholm K Yang LB Yue X Citron M 2004 Amyloid β peptide load is correlated with increased β-secretase activity in sporadic Alzheimer's disease patients. Proc Natl Acad Sci USA 101 3632 3637 14978286 PMC373514
- Not checked yetcites [25] Yang LB Lindholm K Yan R Citron M Xia W 2003 Elevated β-secretase expression and enzymatic activity detected in sporadic Alzheimer disease. Nat Med 9 3 4 12514700
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“previous studies also showed that the effects of BACE1+/− deletion in reducing total Aβ levels and plaque load in PDAPP transgenic mice become smaller during the course of disease progression [20]”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Discussion
What the sources say
- Not checked yetcites [20] McConlogue L Buttini M Anderson JP Brigham EF Chen KS 2007 Partial reduction of BACE1 has dramatic effects on Alzheimer plaque and synaptic pathology in APP transgenic mice. J Biol Chem 282 26326 26334 17616527
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“complete deletion of BACE1 (BACE1−/−), which abrogates Aβ production, can still rescue impaired spontaneous alternation performance concomitant with the prevention of Aβ deposition and neuronal loss in 5XFAD mice at this advanced age [9].”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Discussion
What the sources say
- Not checked yetcites [9] Ohno M Cole SL Yasvoina M Zhao J Citron M 2007 BACE1 gene deletion prevents neuron loss and memory deficits in 5XFAD APP/PS1 transgenic mice. Neurobiol Dis 26 134 145 17258906 PMC1876698
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In the paper
“spontaneous alternation in the Y-maze that represents a measure of spatial working memory [34]”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Results > Abilities of partial BACE1 reduction to rescue memory dysfunction decline with age in 5XFAD mice
What the sources say
- Not checked yetcites [34] Lalonde R 2002 The neurobiological basis of spontaneous alternation. Neurosci Biobehav Rev 26 91 104 11835987
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“recent studies suggest that phosphorylation of the eukaryotic translation initiation factor-2α (eIF2α) plays an important role in mediating the post-transcriptional upregulation of BACE1 in human AD and 5XFAD mouse brains [32], [33].”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Introduction
What the sources say
- Not checked yetcites [32] Chang RC Wong AK Ng HK Hugon J 2002 Phosphorylation of eukaryotic initiation factor-2α (eIF2α) is associated with neuronal degeneration in Alzheimer's disease. Neuroreport 13 2429 2432 12499843
- Not checked yetcites [33] O'Connor T Sadleir KR Maus E Velliquette RA Zhao J 2008 Phosphorylation of the translation initiation factor eIF2α increases BACE1 levels and promotes amyloidogenesis. Neuron 60 988 1009 19109907 PMC2667382
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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
“Together, our results indicate that partial reduction of BACE1 is not sufficient to block the phospho-eIF2α-dependent BACE1 elevation during the progression of AD, thus limiting its abilities to reduce cerebral Aβ/C99 levels and rescue memory deficits and cholinergic neurodegeneration.”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Abstract
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- Rests on an assumption: Approximately 50% BACE1 suppression is likely efficacious.
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In the paper
“genetic deletion of BACE1 prevents AD-like pathologies and improves cognitive impairments in different transgenic mouse models [7], [8], [9], [10].”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Introduction
What the sources say
- Not checked yetcites [7] Ohno M Sametsky EA Younkin LH Oakley H Younkin SG 2004 BACE1 deficiency rescues memory deficits and cholinergic dysfunction in a mouse model of Alzheimer's disease. Neuron 41 27 33 14715132
- Not checked yetcites [8] Ohno M Chang L Tseng W Oakley H Citron M 2006 Temporal memory deficits in Alzheimer's mouse models: rescue by genetic deletion of BACE1. Eur J Neurosci 23 251 260 16420434
- Not checked yetcites [9] Ohno M Cole SL Yasvoina M Zhao J Citron M 2007 BACE1 gene deletion prevents neuron loss and memory deficits in 5XFAD APP/PS1 transgenic mice. Neurobiol Dis 26 134 145 17258906 PMC1876698
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. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“the β-secretase (BACE1: β-site amyloid precursor protein cleaving enzyme 1), which is responsible for initiating the production of Aβ, represents an excellent therapeutic target for the treatment of AD [3], [4], [5], [6].”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Introduction
What the sources say
- Not checked yetcites [3] Citron M 2004 β-Secretase inhibition for the treatment of Alzheimer's disease–promise and challenge. Trends Pharmacol Sci 25 92 97 15102495
- Not checked yetcites [4] Ohno M 2006 Genetic and pharmacological basis for therapeutic inhibition of β- and γ-secretases in mouse models of Alzheimer's memory deficits. Rev Neurosci 17 429 454 17139843
- Not checked yetcites [5] Ohno M 2008 β-Secretase as a prime therapeutic target for Alzheimer's disease: a perspective from mouse model studies. Araki W Recent Advances in the Biology of Secretases, Key Proteases in Alzheimer's Disease Kerala Research Signpost 1 25
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.
None of the sources cited for this claim have been checked yet.
In the paper
“The septohippocampal cholinergic pathway has an established role in mediating spatial working memory including spontaneous alternation performance in the Y-maze [35], [36], [37].”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Results > Abilities of partial BACE1 reduction to rescue cholinergic neurodegeneration decline with age in 5XFAD mice
What the sources say
- Not checked yetcites [35] Ohno M Yamamoto T Watanabe S 1992 Effects of intrahippocampal injections of N-methyl-D-aspartate receptor antagonists and scopolamine on working and reference memory assessed in rats by a three-panel runway task. J Pharmacol Exp Ther 263 943 950 1361577
- Not checked yetcites [36] Feasey-Truger KJ Li BH ten Bruggencate G 1992 Lesions of the medial septum which produce deficits in working/spatial memory do not impair long-term potentiation in the CA3 region of the rat hippocampus in vivo. Brain Res 591 296 304 1446243
- Not checked yetcites [37] Chang Q Gold PE 2004 Impaired and spared cholinergic functions in the hippocampus after lesions of the medial septum/vertical limb of the diagonal band with 192 IgG-saporin. Hippocampus 14 170 179 15098723
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.
Probably not a substantial claim.
None of the sources cited for this claim have been checked yet.
In the paper
“At ≥9 months of age, 5XFAD mice show severe memory deficits together with further developed Aβ pathology and marked synaptic degeneration and neuronal loss [9], [21], [28], [30], [31].”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Introduction
What the sources say
- Not checked yetcites [9] Ohno M Cole SL Yasvoina M Zhao J Citron M 2007 BACE1 gene deletion prevents neuron loss and memory deficits in 5XFAD APP/PS1 transgenic mice. Neurobiol Dis 26 134 145 17258906 PMC1876698
- Not checked yetcites [21] Devi L Ohno M 2010 Genetic reductions of β-site amyloid precursor protein-cleaving enzyme 1 and amyloid-β ameliorate impairment of conditioned taste aversion memory in 5XFAD Alzheimer's disease model mice. Eur J Neurosci 31 110 118 20092558 PMC2887274
- Not checked yetcites [28] Oakley H Cole SL Logan S Maus E Shao P 2006 Intraneuronal β-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer's disease mutations: potential factors in amyloid plaque formation. J Neurosci 26 10129 10140 17021169 PMC6674618
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.
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
“However, these phenotypes are not observed in BACE1+/− knockout mice, suggesting that potential mechanism-based side effects might occur only in completely abolishing BACE1 activity but not in partially inhibiting it.”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > 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.
It may state two separate claims as one.
- Rests on an assumption: These phenotypes (liabilities of complete BACE1 deletion) are not observed in BACE1+/− knockout mice.
None of the sources cited for this claim have been checked yet.
In the paper
“In line with the discovery of various BACE1 physiological substrates besides APP such as neuregulins and β-subunits of the voltage-gated sodium channel, recent studies reveal some liabilities of complete BACE1 deletion including hypomyelination and altered synaptic functions or neuronal activities [4], [5], [6].”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Discussion
What the sources say
- Not checked yetcites [4] Ohno M 2006 Genetic and pharmacological basis for therapeutic inhibition of β- and γ-secretases in mouse models of Alzheimer's memory deficits. Rev Neurosci 17 429 454 17139843
- Not checked yetcites [5] Ohno M 2008 β-Secretase as a prime therapeutic target for Alzheimer's disease: a perspective from mouse model studies. Araki W Recent Advances in the Biology of Secretases, Key Proteases in Alzheimer's Disease Kerala Research Signpost 1 25
- Not checked yetcites [6] Cole SL Vassar R 2007 The Alzheimer's disease β-secretase enzyme, BACE1. Mol Neurodegener 2 22 18005427 PMC2211305
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.
None of the sources cited for this claim have been checked yet.
In the paper
“accumulation of the amyloid-β (Aβ) peptide plays a central role in triggering a pathogenic cascade ultimately leading to neuronal death and profound memory deficits [1], [2].”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Introduction
What the sources say
- Not checked yetcites [1] Hardy JA Higgins GA 1992 Alzheimer's disease: the amyloid cascade hypothesis. Science 256 184 185 1566067
- Not checked yetcites [2] Hardy J Selkoe DJ 2002 The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 297 353 356 12130773
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.
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
“but also indicate that neurotoxic Aβ42 and/or C99 species are responsible for killing cholinergic neurons.”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Discussion
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.
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
“Notably, phosphorylation of eIF2α, which increases age-dependently and induces BACE1 elevation in the 5XFAD model, seems to be important for determining the abilities of partial BACE1 reduction to improve cholinergic and mnemonic deficits.”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > 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.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Interestingly, transgenic overexpression or central administration of the potentially amyloidogenic C99 fragments has been reported to induce memory defects and neurodegeneration [45], [46], [47], [48], [49].”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Discussion
What the sources say
- Not checked yetcites [45] Lee KW Im JY Song JS Lee SH Lee HJ 2006 Progressive neuronal loss and behavioral impairments of transgenic C57BL/6 inbred mice expressing the carboxy terminus of amyloid precursor protein. Neurobiol Dis 22 10 24 16289866
- Not checked yetcites [46] Nalbantoglu J Tirado-Santiago G Lahsaini A Poirier J Goncalves O 1997 Impaired learning and LTP in mice expressing the carboxy terminus of the Alzheimer amyloid precursor protein. Nature 387 500 505 9168112
- Not checked yetcites [47] Berger-Sweeney J McPhie DL Arters JA Greenan J Oster-Granite ML 1999 Impairments in learning and memory accompanied by neurodegeneration in mice transgenic for the carboxyl-terminus of the amyloid precursor protein. Brain Res Mol Brain Res 66 150 162 10095087
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.
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
“All experiments were done blind with respect to the genotype of the mice at 6 and 15–18 months of age, and were conducted with the approval of the Nathan Kline Institute Animal Care and Use Committee (AP2008-268).”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Materials and Methods > Animals
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.
None of the sources cited for this claim have been checked yet.
In the paper
“Consistent with the so-called “cholinergic hypothesis” of AD [50], several APP transgenic mouse models reproduce cholinergic neurodegeneration as evidenced by dystrophic neurites, decreased fiber density in the hippocampus and cortex, and reductions in the medial septum and basal forebrain neuron volume/number [51], [52], [53], [54];”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Discussion
What the sources say
- Not checked yetcites [51] Bellucci A Luccarini I Scali C Prosperi C Giovannini MG 2006 Cholinergic dysfunction, neuronal damage and axonal loss in TgCRND8 mice. Neurobiol Dis 23 260 272 16766197
- Not checked yetcites [52] Christensen DZ Bayer TA Wirths O 2010 Intracellular Aβ triggers neuron loss in the cholinergic system of the APP/PS1KI mouse model of Alzheimer's disease. Neurobiol Aging 31 1153 1163 18771817
- Not checked yetcites [53] Boncristiano S Calhoun ME Kelly PH Pfeifer M Bondolfi L 2002 Cholinergic changes in the APP23 transgenic mouse model of cerebral amyloidosis. J Neurosci 22 3234 3243 11943824 PMC6757538
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
“The failure of BACE1+/− ablation to rescue the septohippocampal degeneration found in 15–18-month-old 5XFAD mice in parallel with no amelioration of memory function supports the view that Aβ/C99-dependent cholinergic dysfunction represents a critical mechanism responsible for memory impairments in 5XFAD mice.”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Discussion
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.
The paper relies on this without support.
Approximately 50% BACE1 suppression is likely efficacious.
“Given ∼50% BACE1 suppression generally accepted as it is likely efficacious, we used BACE1+/− mice as a model system to evaluate the efficacies of partial and therapeutic inhibition of BACE1.”
The paper relies on this without support.
C99 is a direct β-cleavage metabolite of APP.
“Since C99 is a direct β-cleavage metabolite of APP, the high residual levels of C99 may reflect some accumulating species of C99 (similar to Aβ peptides) that could be less sensitive to reduction by BACE1+/− deletion in 15–18-month-old 5XFAD mice.”
The paper relies on this without support.
These phenotypes (liabilities of complete BACE1 deletion) are not observed in BACE1+/− knockout mice.
“However, these phenotypes are not observed in BACE1+/− knockout mice, suggesting that potential mechanism-based side effects might occur only in completely abolishing BACE1 activity but not in partially inhibiting it.”
The paper relies on this without support.
The mechanisms for cholinergic neuron loss in AD are largely unknown.
“however, the mechanisms for cholinergic neuron loss is yet largely unknown.”
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?
In the citing paper
“Significant memory impairment is observed before six months of age [35,37,38]”
From Centella Asiatica Improves Memory and Promotes Antioxidative Signaling in 5XFAD Mice (2019) · cites this paper as [37]
Statistics recomputed
Every reported test result, recomputed from its test statistic and degrees of freedom. A result shows as not adding up only once an independent check has confirmed it.
- ConsistentF(3, 32) = 4.78reported p < .05 · recomputed p = .007
“F (3,32) = 4.78, p < .05”
- ConsistentF(3, 33) = 11.38reported p < .05 · recomputed p < .001
“F (3,33) = 11.38, p < .05”
- ConsistentF(2, 18) = 8.89reported p < .05 · recomputed p = .002
“F (2,18) = 8.89, p < .05”
- ConsistentF(2, 24) = 10.51reported p < .05 · recomputed p < .001
“F (2,24) = 10.51, p < .05”
- ConsistentF(2, 13) = 9.8reported p < .05 · recomputed p = .003
“F (2,13) = 9.80, p < .05”
- ConsistentF(2, 13) = 8.49reported p < .05 · recomputed p = .004
“F (2,13) = 8.49, p < .05”
- ConsistentF(1, 10) = 7.37reported p < .05 · recomputed p = .022
“F (1,10) = 7.37, p < .05”
- ConsistentF(1, 10) = 10.71reported p < .05 · recomputed p = .008
“F (1,10) = 10.71, p < .05”
- ConsistentF(1, 9) = 2.57reported p = .14 · recomputed p = .143
“F (1,9) = 2.57, p = .14”
- ConsistentF(1, 6) = 48.41reported p < .05 · recomputed p < .001
“F (1,6) = 48.41, p < .05”
- ConsistentF(1, 6) = 23.53reported p < .05 · recomputed p = .003
“F (1,6) = 23.53, p < .05”
- ConsistentF(1, 6) = 2.23reported p = .19 · recomputed p = .186
“F (1,6) = 2.23, p = .19”
- ConsistentF(2, 18) = 11.25reported p < .05 · recomputed p < .001
“F (2,18) = 11.25, p < .05”
- ConsistentF(2, 11) = 31.91reported p < .05 · recomputed p < .001
“F (2,11) = 31.91, p < .05”
- ConsistentF(2, 11) = 25.76reported p < .05 · recomputed p < .001
“F (2,11) = 25.76, p < .05”
- ConsistentF(2, 21) = 11.72reported p < .05 · recomputed p < .001
“F (2,21) = 11.72, p < .05”
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Self-check results appear here once an independent check has confirmed them.
Citations
Cites
The mouse brain in stereotaxic coordinates
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Alzheimer's disease: the amyloid cascade hypothesis
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“in triggering a pathogenic cascade ultimately leading to neuronal death and profound memory deficits [1,2].”
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BACE1 is the major β-secretase for generation of Aβ peptides by neurons
Cai, H., Wang, Y., McCarthy, D. B., Wen, H., Borchelt, D., Price, D. L., & Wong, P. C. (2001) · Nature Neuroscience · doi:10.1038/85064 · Cited by 1,087
The neurobiological basis of spontaneous alternation
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“represents a measure of spatial working memory [34] (Fig.”
BackgroundThe secretases: enzymes with therapeutic potential in Alzheimer disease
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Elevated β-secretase expression and enzymatic activity detected in sporadic Alzheimer disease
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Cited by
Sorted by citations
Microglia in Neuroinflammation and Neurodegeneration: From Understanding to Therapy
Muzio, L., Viotti, A., & Martino, G. (2021) · Frontiers in Neuroscience · doi:10.3389/fnins.2021.742065 · Cited by 581
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“…laboratory and others have demonstrated that elevations in BACE1 have an important role in accelerating disease progression in 5XFAD mouse brains (Devi and Ohno, 2010b; O'Connor et al, 2008; Ohno et al, 2007; Zhang et al, 2009; Zhao et al, 2007) as well as in sporadic AD brains (Fukumoto et al,…”
BackgroundMethodResultInfluentialSelf-citationGenetic mouse models of brain ageing and Alzheimer's disease
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Aβ reduction in BACE1 heterozygous null 5XFAD mice is associated with transgenic APP level
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“The BACE1 heterozygous null mouse is a useful model for 50% BACE1 inhibition, and several publications have described BACE1 mice on various backgrounds of APP transgenic mouse models, with most observing some reduction in Aβ levels, but the degree of Aβ lowering varies from model to model [5,14,21-26].”
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“7C,D), which is consistent with the published reports (Ohno et al., 2007; Zhao et al., 2007; Devi and Ohno, 2010; Devi et al., 2010, 2012; Ho et al., 2012).”
BackgroundResultInfluentialChallenges for Alzheimer's Disease Therapy: Insights from Novel Mechanisms Beyond Memory Defects
Frozza, R. L., Lourenco, M. V., & Felice, F. G. D. (2018) · Frontiers in Neuroscience · doi:10.3389/fnins.2018.00037 · Cited by 211
“Furthermore, it has been recently demonstrated that AβOs stimulates eIF2α phosphorylation (Devi and Ohno, 2010, 2013, 2014; Lourenco et al., 2013; Ma et al., 2013; Baleriola et al., 2014).”
BackgroundUpdates on mouse models of Alzheimer’s disease
Zhong, M. Z., Peng, T., Duarte, M. L., Wang, M., & Cai, D. (2024) · Molecular Neurodegeneration · doi:10.1186/s13024-024-00712-0 · Cited by 189
“Behavior impairments were seen in 5xFAD mice with impaired spatial working memory measured by the Y-maze test by 4–5 months of age [78, 81], as well as impaired spatial memory at 4–5 months of age detected by the Morris water maze tests [84] and contextual-fear-conditioning tests [85].”
BackgroundMethodOxidative stress increases BACE1 protein levels through activation of the PKR-eIF2α pathway
Mouton‐Liger, F., Paquet, C., Dumurgier, J., Bouras, C., Pradier, L., Gray, F., & Hugon, J. (2012) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2012.01.009 · Cited by 174
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“Two sections per mouse taken at levels between −1.7 and −1.9 mm to bregma according to the mouse brain atlas of (Franklin and Paxinos, 2008) were stained by the avidin-biotin peroxidase complex (ABC) method as described previously (Devi et al., 2010; Devi and Ohno, 2010a; Kimura et al., 2010).”
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Activation of mTOR: a culprit of Alzheimer’s disease?
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“Sandwich antibody ELISAs were performed as described previously [35,36].”
MethodPang, K., Jiang, R., Zhang, W., Yang, Z., Li, L., Shimozawa, M., Tambaro, S., Mayer, J., Zhang, B., Li, M., et al. (2021) · Cell Research · doi:10.1038/s41422-021-00582-x · Cited by 144
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“The 5xFAD mice develop aggressive amyloid pathology and showed cognitive deficits across multiple domains around 4–5 months of age [18, 24, 36, 52].”
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“…demonstrated that the abilities of BACE1 +/− deletion to reduce Aβ levels or plaque load in brains of APP transgenic mice including the 5XFAD model become smaller and eventually disappear during the course of disease progression (Devi and Ohno, 2010b; Laird et al., 2005; McConlogue et al., 2007).”
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Sanchez-Varo, R. M., Mejias‐Ortega, M., Fernandez-Valenzuela, J. J., Nuñez‐Diaz, C., Cáceres-Palomo, L., Vegas‐Gomez, L., Sánchez‐Mejías, E., Trujillo‐Estrada, L., García‐León, J. A., Moreno‐González, I., et al. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23105404 · Cited by 134
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“Increases in phospho-eIF2a levels occur in brains of sporadic AD and advanced pathological stages of APP transgenic mice including the 5XFAD model [24-26,45,46] and are shown to correlate with BACE1 elevation [25,26].”
BackgroundResultInfluentialSelf-citationRoles of eIF2α kinases in the pathogenesis of Alzheimer’s disease
Ohno, M. (2014) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2014.00022 · Cited by 123
“…in eIF2α phosphorylation is successfully recapitulated in different transgenic mouse models of AD that exhibit memory impairments, including 5XFAD (O’Connor et al., 2008; Devi and Ohno, 2010, 2013a,b), Tg2576 (Kim et al., 2007), and APP/PS1 KI (Page et al., 2006; Mouton-Liger et al., 2012).”
BackgroundInfluentialSelf-citationFelice, F. G. D., & Lourenco, M. V. (2015) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2015.00094 · Cited by 122
“It is noteworthy that activation of PKR/eIF2α-P signaling (O’Connor et al., 2008; Devi and Ohno, 2010; Mouton-Liger et al., 2012a), as well as high-fat diet-induced metabolic stress (Wang et al., 2013) was shown to promote amyloidogenesis in a feed-forward cycle that might exacerbate amyloid…”
BackgroundGu, X., Xu, L.-J., Liu, Z., Wei, B., Yang, Y., Xu, G., Yin, X., & Wang, W. (2016) · Behavioural Brain Research · doi:10.1016/j.bbr.2016.05.052 · Cited by 114
Abnormal vibrissa‐related behavior and loss of barrel field inhibitory neurons in 5xFAD transgenics
Flanigan, T. J., Xue, Y., Kishan Rao, S., Dhanushkodi, A., & McDonald, M. P. (2014) · Genes, Brain and Behavior · doi:10.1111/gbb.12133 · Cited by 104
“…the 5xFAD transgenics also exhibit robust age-related neuronal loss in the subiculum, cortical layer V and the medial septum/vertical limb of the diagonal band (Devi & Ohno 2010; Eimer & Vassar 2013; Jawhar et al. 2012; Joyashiki et al. 2011; Moon et al. 2012; Oakley et al. 2006; Ohno et al. 2007).”
BackgroundAdult hippocampal neurogenesis and its impairment in Alzheimer’s disease
Kim, T. A., Syty, M. D., Wu, K., & Ge, S. (2022) · 动物学研究 · doi:10.24272/j.issn.2095-8137.2021.479 · Cited by 116
An Update of Animal Models of Alzheimer Disease with a Reevaluation of Plaque Depositions
Lee, J. E., & Han, P. (2013) · Experimental Neurobiology · doi:10.5607/en.2013.22.2.84 · Cited by 101
EFAD transgenic mice as a human APOE relevant preclinical model of Alzheimerʼns disease
Tai, L. M., Balu, D., Avila-Munoz, E., Abdullah, L., Thomas, R., Collins, N., Valencia-Olvera, A. C., & LaDu, M. J. (2017) · Journal of Lipid Research · doi:10.1194/jlr.r076315 · Cited by 93
Centella Asiatica Improves Memory and Promotes Antioxidative Signaling in 5XFAD Mice
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“Significant memory impairment is observed before six months of age [35,37,38], months before pathology and cognitive deficiencies develop in Tg2576.”
BackgroundMetabolic Dysfunction in Alzheimer’s Disease: From Basic Neurobiology to Clinical Approaches
Clarke, J. R., Ribeiro, F. C., Frozza, R. L., Felice, F. G. D., & Lourenco, M. V. (2018) · Journal of Alzheimer s Disease · doi:10.3233/jad-179911 · Cited by 92
The PERK-Dependent Molecular Mechanisms as a Novel Therapeutic Target for Neurodegenerative Diseases
Rozpędek-Kamińska, W., Siwecka, N., Wawrzynkiewicz, A., Wojtczak, R., Pytel, D., Diehl, J. A., & Majsterek, I. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21062108 · Cited by 84
Behaviour Hallmarks in Alzheimer’s Disease 5xFAD Mouse Model
Pádua, M. S., Guil‐Guerrero, J. L., & Lopes, P. A. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25126766 · Cited by 87
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“It should be noted that in the 5XFAD model the 6E10-reactive species include full-length APP, C-terminal fragments (CTFs) and a diverse range of smaller and modified Aβ peptides [22-24].”
Neuron Loss in Alzheimer’s Disease: Translation in Transgenic Mouse Models
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“In good agreement, 6-month-old mice overexpressing APP with the Swedish and London mutations revealed an ~60% decrease in the number of ChAT-positive cells in the nbM [45] and reduced ChAT-positive neuron numbers were also reported in the medial septum of 3xTg [58] and 5xFAD mice [136].”
BackgroundAPOE4 confers transcriptomic and functional alterations to primary mouse microglia
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“, 2002) as well as mouse models harboring mutations that cause early-onset autosomal dominant AD and exhibiting amyloid pathology (Devi and Ohno, 2010; MoutonLiger et al., 2015; Segev et al., 2013).”
BackgroundLourenco, M. V., Ferreira, S. T., & Felice, F. G. D. (2015) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2015.03.003 · Cited by 74
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“Notably, 5xFAD transgenic mice are phenotypically different from APP/PS1 mice [103,104] in that without forming Tau aggregates, they develop amyloid pathology early at six weeks of age and spatial memory impairment when they are about four months old [77,105], thus reflecting relatively expedited progression of AD.”
BackgroundDevi, L., & Ohno, M. (2013) · PLoS ONE · doi:10.1371/journal.pone.0077335 · Cited by 66
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“2017 eNeuro.org et al., 2008; Devi and Ohno, 2010; Scheper and Hoozemans, 2015).”
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Chronic 5-HT4 receptor activation decreases Aβ production and deposition in hAPP/PS1 mice
Tesseur, I. C., Pimenova, A. A., Lo, A. C., Ciesielska, M., Lichtenthaler, S. F., Maeyer, J. H. D., Schuurkes, J. A. J., D’Hooge, R., & Strooper, B. D. (2013) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2013.01.020 · Cited by 63
ER stress is not elevated in the 5XFAD mouse model of Alzheimer's disease
Sadleir, K. R., Popović, J., & Vassar, R. J. (2018) · Journal of Biological Chemistry · doi:10.1074/jbc.ra118.005769 · Cited by 61
Age-related changes in social behaviours in the 5xFAD mouse model of Alzheimer’s disease
Kosel, F., Muñoz, P., Yang, J., Wong, A. A., & Franklin, T. B. (2019) · Behavioural Brain Research · doi:10.1016/j.bbr.2019.01.029 · Cited by 57
In Silico ADME Profiling of Salubrinal and Its Analogues
Zadorozhnii, P. V., Kiselev, V. V., & Kharchenko, A. V. (2022) · Future Pharmacology · doi:10.3390/futurepharmacol2020013 · Cited by 65
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Self-citationRheb Inhibits Protein Synthesis by Activating the PERK-eIF2α Signaling Cascade
Tyagi, R., Shahani, N., Gorgen, L., Ferretti, M., Pryor, W., Chen, P. Y., Swarnkar, S., Worley, P. F., Karbstein, K., Snyder, S. H., et al. (2015) · Cell Reports · doi:10.1016/j.celrep.2015.01.014 · Cited by 51
“PERK and phospho-eIF2α levels are linked to BACE1 regulation and AD-related behavioral deficits (Devi and Ohno, 2010; Ma et al., 2013; O'Connor et al., 2008).”
BackgroundOhno, M. (2016) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2016.04.007 · Cited by 50
Self-citationYan, L., Deng, Y., Gao, J., Liu, Y., Li, F., Shi, J., & Gong, Q. (2017) · Frontiers in Pharmacology · doi:10.3389/fphar.2017.00106 · Cited by 50
“The phosphorylation level of eIF2α positively correlated with BACE1 expression level, which can increased the protein level of BACE1 in 5 × FAD mice (Devi and Ohno, 2012, 2013).”
BackgroundEnhanced delivery of a low dose of aducanumab via FUS in 5×FAD mice, an AD model
Kong, C., Yang, E.-J., Shin, J., Park, J., Kim, S., Park, S., Chang, W. S., Lee, C., Kim, H.-J., Kim, H.-S., et al. (2022) · Translational Neurodegeneration · doi:10.1186/s40035-022-00333-x · Cited by 52
Translational control by eIF2α in neurons: Beyond the stress response
Bellato, H. M., & Hajj, G. N. M. (2016) · Cytoskeleton · doi:10.1002/cm.21294 · Cited by 46
“The increased phosphorylation of eIF2a can also be reproduced in both AD cell [Chang et al., 2002a; Kim et al., 2010] and mouse models [Page et al., 2006; Kim et al., 2007; O’Connor et al., 2008; Devi and Ohno, 2010, 2013a,b 2014; Mouton-Liger et al., 558 Bellato and Hajj CYTOSKELETON 2012].”
BackgroundAngeli, S., Kousiappa, I., Stavrou, M., Sargiannidou, I., Georgiou, E., Papacostas, S., & Kleopa, K. A. (2020) · Frontiers in Neuroscience · doi:10.3389/fnins.2020.582934 · Cited by 45
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“Accordingly, we performed the assay by focusing on eIF2a signaling, because eIF2a phosphorylation is tightly linked to BACE1 translation and further the protein level (Devi and Ohno, 2010; Rozpedek et al., 2015).”
Panagaki, T., Gengler, S., & Hölscher, C. (2018) · Journal of Alzheimer s Disease · doi:10.3233/jad-180584 · Cited by 41
“PERK over-activation can further elevate the expression of the (cid:2) -site amyloid precursor protein cleaving enzyme 1 (BACE-1) to accelerate amyloidogenesis [88, 114, 115].”
Sadleir, K. R., Eimer, W. A., Kaufman, R. J., Osten, P., & Vassar, R. J. (2014) · PLoS ONE · doi:10.1371/journal.pone.0101643 · Cited by 40
“Another group has reported that p-eIF2a levels are increased ,3and ,9-fold at 6 and 15–18 months of age, respectively [69].”
BackgroundMechanisms that lessen benefits of β-secretase reduction in a mouse model of Alzheimer’s disease
Devi, L., & Ohno, M. (2013) · Translational Psychiatry · doi:10.1038/tp.2013.59 · Cited by 38
“ciated with BACE1 haploinsufficiency decline with age or the progression of disease in APP transgenic mice.(11,22,25,26)”
BackgroundResultInfluentialSelf-citationMamada, N., Tanokashira, D., Hosaka, A., Kametani, F., Tamaoka, A., & Araki, W. (2015) · Molecular Brain · doi:10.1186/s13041-015-0163-5 · Cited by 40
“BACE1 levels and activity are increased in the brains of AD patients [9–15] and mouse models of AD [15–17], supporting the involvement of aberrant BACE1 in AD pathogenesis.”
BackgroundA combination Alzheimer’s therapy targeting BACE1 and neprilysin in 5XFAD transgenic mice
Devi, L., & Ohno, M. (2015) · Molecular Brain · doi:10.1186/s13041-015-0110-5 · Cited by 37
“However, some of these studies raise concern that the beneficial outcomes associated with partial BACE1 inhibition may decline during the progression of AD [11,12,15,16,18,21].”
BackgroundResultInfluentialSelf-citationMultiscale proteomic modeling reveals protein networks driving Alzheimer’s disease pathogenesis
Wang, E., Yu, K., Cao, J., Wang, M., Katsel, P., Song, W., Wang, Z., Li, Y., Wang, X., Wang, Q., et al. (2025) · Cell · doi:10.1016/j.cell.2025.08.038 · Cited by 45
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Potential roles of the endoplasmic reticulum stress pathway in amyotrophic lateral sclerosis
Jeon, Y., Kwon, Y., Lee, S., & Kim, H. (2023) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2023.1047897 · Cited by 34
Eremenko, E., Mittal, K., Berner, O., Kamenetsky, N., Nemirovsky, A., Elyahu, Y., & Monsonego, A. (2019) · EBioMedicine · doi:10.1016/j.ebiom.2019.04.019 · Cited by 32
A metabolic perspective of late onset Alzheimer’s disease
Ettcheto, M., Cano, A. C., Busquets, O., Manzine, P. R., Sánchez‐López, E., Castro-Torres, R. D., Beas‐Zárate, C., Verdaguer, E., García, M. L., Olloquequi, J., et al. (2019) · Pharmacological Research · doi:10.1016/j.phrs.2019.104255 · Cited by 31
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“Furthermore, significant cholinergic neuronal loss of the MS was demonstrated in the 6-month-old 5XFAD mice with cognitive dysfunction [46].”
BackgroundDevi, L., Tang, J., & Ohno, M. (2015) · Current Alzheimer Research · doi:10.2174/1567205012666141218125042 · Cited by 28
“However, it should be noted that the beneficial effects of BACE1 haploinsufficiency in AD transgenic mice dramatically decline with age or the progression of disease [13, 16, 17, 19].”
BackgroundMethodInfluentialSelf-citationFructus mume extracts alleviate cognitive impairments in 5XFAD transgenic mice
Park, J.-C., Ma, J., Jeon, W. K., & Han, J. (2015) · BMC Complementary and Alternative Medicine · doi:10.1186/s12906-016-1033-0 · Cited by 29
Cholinergic neurodegeneration in Alzheimer disease mouse models
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Post-translational regulation of the β-secretase BACE1
Araki, W. (2016) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2016.04.009 · Cited by 26
Devi, L., & Ohno, M. (2015) · Neuroscience · doi:10.1016/j.neuroscience.2015.08.037 · Cited by 28
“As a mechanism underlying accelerated β-amyloidogenesis in 5XFAD mice with aging, we previously demonstrated that BACE1 expression is significantly elevated (~2-fold relative to wild-type controls) in older 5XFAD mice (≥12 months of age) (Devi and Ohno, 2010b, Devi and Ohno, 2013).”
BackgroundInfluentialSelf-citationFalangola, M. F., Nie, X., Ward, R., Dhiman, S., Voltin, J., Nietert, P. J., & Jensen, J. H. (2021) · Magnetic Resonance Imaging · doi:10.1016/j.mri.2021.06.022 · Cited by 25
Does any drug to treat cancer target mTOR and iron hemostasis in neurodegenerative disorders?
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“On the other hand eIF2a increase BACE expression which leads to Ab formation (Devi and Ohno 2010) (Fig.”
BackgroundOlfactory Evaluation in Alzheimer’s Disease Model Mice
Zhang, J., Zhao, Z., Sun, S., Li, J., Wang, Y., Dong, J., Yang, S. C., Lou, Y., Yang, J., Li, W., et al. (2022) · Brain Sciences · doi:10.3390/brainsci12050607 · Cited by 19
Bayesian Estimation Of Clipped Gaussian Processes With Application To Ofdm
Banelli, P., Leus, G. J. T., & Giannakis, G. B. (2002) · doi:10.5281/zenodo.37796 · Cited by 20
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“Mice were placed into the centre of the maze (3 arms at a 120 ̊ angle from each other, arms 30cm long and 10cm wide; walls and floor opaque and 10cm high) and their behaviour video-recorded for 5 min [39] or 8 minutes [26, 44, 45] for subsequent analysis.”
MethodLansdell, T. A., Xu, H., Galligan, J., & Dorrance, A. (2023) · Journal of Alzheimer's Disease · doi:10.3233/jad-220905 · Cited by 10
Takuma, K., Mizoguchi, H., Funatsu, Y., Hoshina, Y., Himeno, Y., Fukuzaki, E., Kitahara, Y., Arai, S., Ibi, D., Kamei, H., et al. (2012) · Neuroscience · doi:10.1016/j.neuroscience.2012.01.034 · Cited by 16
“Both BACE1 and ABAD are considered as key molecules in the hippocampal cholinergic dysfunction (Devi and Ohno, 2010; Lustbader et al., 2004).”
Cope, Z. A., Murai, T., & Rizzo, S. J. S. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2022.805063 · Cited by 17
Pechlivanidou, M., Kousiappa, I., Angeli, S., Sargiannidou, I., Koupparis, A. M., Papacostas, S., & Kleopa, K. A. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232415597 · Cited by 14
Reduced social investigation and increased injurious behavior in transgenic 5xFAD mice
Kosel, F., Hamilton, J. S., Harrison, S. L., Godin, V., & Franklin, T. B. (2020) · Journal of Neuroscience Research · doi:10.1002/jnr.24578 · Cited by 14
“…PSD-95 (synaptic membrane-associated proteins), indicating significant synaptic degeneration and impaired signaling (Crouzin et al., 2013; Crowe & Ellis-Davies, 2014; Devi & Ohno, 2010; Eimer & Vassar, 2013; Jawhar, Trawicka, Jenneckens, Bayer, & Wirths, 2012; Li et al., 2013; Oakley et al., 2006).”
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Guix, F. X., Sartório, C. L., & ILL‐Raga, G. (2019) · Journal of Alzheimer s Disease Reports · doi:10.3233/adr-180089 · Cited by 13
Forebrain depletion of Rheb GTPase elicits spatial memory deficits in mice
Shahani, N., Huang, W., Varnum, M. M., Page, D. T., & Subramaniam, S. (2016) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2016.11.006 · Cited by 11
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Ali, T., Klein, A. N., Vu, A. P., Arifin, M. I., Hannaoui, S., & Gilch, S. (2023) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-023-04785-w · Cited by 11
“It is well-known that the 5XFAD model is ideal to assess the amount of AβO and Aβ plaques [39, 41].”
BackgroundYang, S.-G., Wang, S.-W., Zhao, M., Zhang, R., Zhou, W.-W., Li, Y.-N., Su, Y.-J., Zhang, H., Yu, X.-L., & Liu, R.-T. (2012) · PLoS ONE · doi:10.1371/journal.pone.0048540 · Cited by 10
“Partial reduction of BACE1 is not sufficient to block the BACE1 elevation during the progression of AD, thus limiting its abilities to reduce cerebral Ab/C99 levels and rescue memory deficits and cholinergic neurodegeneration [67].”
BackgroundLi, J., Yang, M., Dai, Y., Guo, X., Ding, Y., Li, X., Zhang, S., Xu, W., Chen, L., Tao, J., et al. (2024) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.14743 · Cited by 10
“36–39 The hippocampus primarily receives dense cholinergic projections from the MS and VDB nuclei of the basal forebrain, forming the basal fore - brain hippocampal circuit.”
BackgroundSvensson, M., Olsson, G., Yang, Y., Bachiller, S., Ekemohn, M., Ekstrand, J., & Deierborg, T. (2021) · Scientific Reports · doi:10.1038/s41598-021-83998-0 · Cited by 8
Lazarev, V. F., Dutysheva, E. A., Mikhaylova, E. R., Trestsova, M. A., Utepova, I. A., Чупахин, О. Н., Margulis, B. A., & Guzhova, I. V. (2022) · Molecules · doi:10.3390/molecules27248950 · Cited by 8
“At the P180 time point, when, according to the literature data, signs of AD can already be observed, such as amyloid deposits in the hippocampus [22,23], the animals were divided into four groups: (1) ‘untreated wt’ mice (n = 10); (2) wt mice treated with IA-50 (‘wt-IA-50’) (n = 10); (3) ‘untreated 5xFAD’ mice (n = 10…”
Lee, M. K., & Chen, G. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25095004 · Cited by 6
“Some studies show a loss of Ach afferents but no loss of Ach neurons [8,17], while the analysis of the APP NL-G-F and the 5X FAD models shows a significant loss of Ach neurons [14,18].”
BackgroundResultHyperbaric oxygen alleviates selective domains of cognitive and motor deficits in female 5xFAD mice
Mensah-Kane, P., Davis, D., Shi, H. S., Trinh, O. T. P., Vann, P. H., Dory, L., & Sumien, N. (2023) · GeroScience · doi:10.1007/s11357-023-01047-2 · Cited by 7
“The genotype differences observed in our study are consistent with prior observations of the 5xFAD model, where these transgenic mice consistently exhibit cognitive impairments [17, 25–27] and motor deficits [28, 29] compared to wild-type (WT) mice.”
Animal Models of Alzheimer’s Disease
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Harnessing viral strategies to reverse cognitive dysfunction through the integrated stress response
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Metadata
- Authors
- Devi, L., & Ohno, M.
- Affiliations
- New York University (US)
- Corresponding author
- Ohno, Masuo
- ORCID
- Ohno, Masuo
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2010-09-23
- Volume
- 5
- Issue
- 9
- Pages
- e12974
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC2944882
- OpenAlex
- W2012590437
- Cited by
- 140
- References
- 61
- Citations by year
- 2026: 8 · 2025: 8 · 2024: 14 · 2023: 9 · 2022: 16 · 2021: 11 · 2020: 8 · 2019: 8 · 2018: 5 · 2017: 9 · 2016: 6 · 2015: 12 · 2014: 10 · 2013: 6 · 2012: 4
- FWCI
- 3.25
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Alzheimer's Association (IIRG-08-91231)
- National Institutes of Health
- National Institute of Mental Health (R01MH067251)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Pharmacology (medical) › Cholinesterase and Neurodegenerative Diseases
- Keywords
- eIF2α phosphorylation, Alzheimer's disease, 5xFAD mice, amyloid-beta, cholinergic neurodegeneration, memory impairment, C99, amyloid-beta 42, translation initiation, gene dosage, BACE1 inhibition
- MeSH terms
- Alzheimer Disease, Animals, Cholinergic Fibers, Disease Models, Animal, Female, Humans, Male, Memory, Mice, Inbred C57BL, Mice, Transgenic, Nerve Degeneration, Phosphorylation, Eukaryotic Initiation Factor-2, Aspartic Acid Endopeptidases, Mice, Knockout, Mice, Amyloid Precursor Protein Secretases
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 2026-10-10, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-10 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
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.
What counts as a claim ›How we measure confidence ›How we check this ›
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