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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- Findingown data
ChAT levels in the hippocampus of both 5XFAD and BACE1+/−·5XFAD mice at 15-18 months of age are significantly lower than those of wild-type control mice.
“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)”
Quote in the paperSubstantial claim - Findingown data
Aβ42 levels are not significantly different between BACE1+/−·5XFAD and 5XFAD mice at 15-18 months of age.
“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).”
Quote in the paperSubstantial claim - Findingown data
BACE1+/− ablation significantly lowers excessive Aβ42 levels in 6-month-old 5XFAD mouse brains.
“BACE1+/− ablation significantly lowered excessive levels of Aβ42 in 6-month-old 5XFAD mouse brains (F (1,6) = 23.53, p<0.05).”
Quote in the paperSubstantial claim - Findingown data
C99 levels are significantly reduced in BACE1+/−·5XFAD mice at 6 months of age compared to 5XFAD mice.
“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)”
Quote in the paperSubstantial claim - Findingown data
There is only a trend toward slight increases in ChAT levels of BACE1+/−·5XFAD mice compared to 5XFAD littermates at 15-18 months of age.
“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).”
Quote in the paperSubstantial claim
- Findingown data
BACE1+/− deletion is no longer able to significantly influence C99 and Aβ42 levels in 15-18-month-old 5XFAD mouse brains, with approximately 18% and 20% reductions, respectively.
“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).”
Quote in the paperSubstantial claim - Findingown data
BACE1+/− deletion rescues spatial working memory deficits to wild-type levels in 5XFAD mice at 6 months of age, as measured by spontaneous alternation.
“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)”
Quote in the paperSubstantial claim - Findingown data
Residual BACE1 levels in older BACE1+/−·5XFAD mouse brains are equivalent to those of wild-type controls.
“the residual levels of BACE1 in older BACE1+/−·5XFAD mouse brains were equivalent to those of wild-type controls.”
Quote in the paperSubstantial claim - Findingown data
Elevated C99 levels are no longer significantly affected by BACE1+/− deletion at 15-18 months of age.
“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).”
Quote in the paperSubstantial claim - Findingown data
C99 levels in 15-18-month-old 5XFAD mouse brains are significantly higher than those of 6-month-old 5XFAD brains, at approximately 172%.
“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)”
Quote in the paperSubstantial claim - Findingown data
ChAT levels in the hippocampus are significantly reduced in 5XFAD mice at 6 months of age compared with wild-type controls.
“ChAT levels were significantly reduced in 5XFAD mice at 6 months of age compared with wild-type controls”
Quote in the paperSubstantial claim - Findingown data
Heterozygous BACE1 knockout reduces cerebral BACE1 expression by approximately 50% in 5XFAD mice at 15-18 months of age.
“Heterozygous gene knockout also reduced cerebral BACE1 expression by ∼50% in 5XFAD mice at this advanced age (p<0.05).”
Quote in the paperSubstantial claim - Findingown data
ChAT is restored to wild-type levels in 5XFAD mice with BACE1+/− genotype at 6 months of age.
“ChAT was restored to wild-type levels in 5XFAD mice with BACE1+/− genotype (F (2,18) = 8.89, p<0.05)”
Quote in the paperSubstantial claim - Findingown data
The number of ChAT-immunoreactive neurons is significantly reduced in 5XFAD mice at 6 months of age compared to wild-type controls.
“Quantitative analysis of ChAT-immunoreactive neurons revealed significant reductions in their number in 5XFAD mice at 6 months of age compared to wild-type controls”
Quote in the paperSubstantial claim - Findingown data
Phospho-eIF2α levels are dramatically elevated, approximately 9-fold relative to wild-type controls, in 15-18-month-old 5XFAD mouse brains.
“phospho-eIF2α levels were dramatically elevated (∼9-fold relative to wild-type controls) in 15–18-momth-old 5XFAD mouse brains in accordance with their remarkable BACE1 elevation (F (2,21) = 11.72, p<0.05)”
Quote in the paperSubstantial claim - Findingown data
At 15-18 months of age, spontaneous alternation is similarly reduced in 5XFAD and BACE1+/−·5XFAD mice compared with age-matched wild-type controls.
“levels of spontaneous alternation was similarly reduced in 5XFAD and BACE1+/−·5XFAD mice compared with those of age-matched wild-type control mice (F (3,33) = 11.38, p<0.05)”
Quote in the paperSubstantial claim - Findingown data
5XFAD mice at 6 months of age show significantly reduced spontaneous alternation performance in the Y-maze compared with wild-type controls.
“5XFAD mice showed significantly reduced levels of spontaneous alternation performance in the Y-maze compared with wild-type controls (p<0.05)”
Quote in the paperSubstantial claim - Findingown data
BACE1 levels are not different between 5XFAD and wild-type mice at 6 months of age.
“BACE1 levels were not different between 5XFAD and wild-type mice at 6 months of age”
Quote in the paperNot a substantial claim - Findingown data
Percent alternation is indistinguishable between BACE1+/− and wild-type mice at 6 or 15-18 months of age.
“the percent alternation was indistinguishable between BACE1+/− and wild-type mice at 6 or 15–18 months of age”
Quote in the paperSubstantial claim - Findingown data
Aβ42 accumulation is dramatically exacerbated in 5XFAD mice from 6 to 15-18 months of age.
“Aβ42 accumulation was also dramatically exacerbated in 5XFAD mice from 6 to 15–18 months of age (F (1,6) = 48.41, p<0.05).”
Quote in the paperNot a substantial claim - Findingown data
BACE1 levels in 15-18-month-old 5XFAD mice are significantly increased up to approximately 200% of those found in age-matched wild-type control mice.
“BACE1 levels in 15–18-month-old 5XFAD mice were significantly increased up to ∼200% of those found in age-matched wild-type control mice (F (2,11) = 31.91, p<0.05)”
Quote in the paperSubstantial claim - Findingown data
Full-length APP expression levels are not affected by BACE1+/− mutation in 5XFAD mice at 6 months or 15-18 months of age.
“the full-length APP expression levels were not affected by BACE1+/− mutation in 5XFAD mice at 6 months or 15–18 months of age”
Quote in the paperNot a substantial claim - Findingown data
BACE1+/− genotype significantly reduces BACE1 expression by approximately 50% in 5XFAD mice at 6 months of age, in concordance with the reduction in gene copy number.
“BACE1+/− genotype significantly reduced BACE1 expression (by ∼50%) in concordance with the reduction in gene copy number in 5XFAD mice at this age (F (2,18) = 11.25, p<0.05)”
Quote in the paperSubstantial claim - Findingown data
Phospho-eIF2α levels in BACE1+/−·5XFAD mice at 15-18 months of age remain strikingly elevated compared with wild-type controls, at approximately 6-fold.
“they remained strikingly elevated compared with wild-type controls (∼6-fold) consistent with the persistent BACE1 upregulation.”
Quote in the paperSubstantial claim - Findingown data
ChAT-positive neurons are less stained in the medial septum and vertical limb of the diagonal band of 5XFAD mice at 6 and 15-18 months of age compared with age-matched wild-type controls.
“ChAT-positive neurons were less stained in these brain regions of 5XFAD mice at 6 months (Fig. 2C) and 15–18 months (Fig. 2D) of age as compared with the respective age-matched wild-type control mice.”
Quote in the paperSubstantial claim - Findingown data
ChAT-positive neuron number is completely restored to wild-type levels in BACE1+/−·5XFAD mice at 6 months of age.
“while ChAT-positive neuron number was completely restored to wild-type levels in BACE1+/−·5XFAD mice (F (2,13) = 9.80, p<0.05)”
Quote in the paperSubstantial claim - Findingown data
Phospho-eIF2α levels in BACE1+/−·5XFAD mice at 15-18 months of age are lower than those of 5XFAD mice.
“Although phospho-eIF2α levels in BACE1+/−·5XFAD mice were lower than those of 5XFAD mice at this advanced age (p<0.05)”
Quote in the paperSubstantial claim - Findingown data
The total number of arm entries during Y-maze testing is not significantly different between the four groups of mice at 6 months or 15-18 months of age.
“the total number of arm entries during Y-maze testing was not significantly different between the four groups of mice tested at 6 months (Fig. 1C) or 15–18 months (Fig. 1D) of age.”
Quote in the paperSubstantial claim - Findingown data
Sal003-induced increases in phospho-eIF2α elevate BACE1 levels in brain slices from 6-month-old 5XFAD mice.
“Sal 003-induced increases in phospho-eIF2α elevated BACE1 levels”
Quote in the paperSubstantial claim - Findingown data
In BACE1+/−·5XFAD mice at advanced age (15-18 months), BACE1 upregulation was attenuated to a certain degree but largely maintained (~6-fold).
“upregulation was attenuated to a certain degree but was largely maintained (∼6-fold) in BACE1+/−·5XFAD mice at this advanced age.”
Quote in the paperSubstantial claim - Findingown data
C99 levels increased substantially in 5XFAD mice at 15-18 months of age (~172%) compared with 6-month-old 5XFAD mice, in line with BACE1 elevation (~200%).
“Meanwhile, C99 levels increased substantially in 5XFAD mice at 15–18 months of age (∼172%) compared with 6-month-old 5XFAD mice in line with the BACE1 elevation (∼200%).”
Quote in the paperSubstantial claim - Findingown data
Levels of full-length APP were not altered in BACE1+/−·5XFAD mice.
“It should also be noted that levels of the full-length APP were not altered in BACE1+/−·5XFAD mice”
Quote in the paperSubstantial claim - Findingown data
BACE1+/− deletion partially suppressed build-up of C99 by ~53% correlating with ~50% BACE1 reductions in 5XFAD mice at 6 months of age.
“BACE1+/− deletion partially suppressed build-up of the β-secretase-cleaved C-terminal fragment C99 (by ∼53%) correlating with ∼50% BACE1 reductions in 5XFAD mice at 6 months of age.”
Quote in the paperSubstantial claim - Findingnone given
5XFAD model mice exhibited hippocampal cholinergic deficits associated with significant neuron loss in the medial septum and the vertical limb of the diagonal band.
“5XFAD model mice exhibited hippocampal cholinergic deficits associated with significant neuron loss in the medial septum and the vertical limb of the diagonal band.”
Quote in the paperSubstantial claim - Findingown data
Directly raising levels of phospho-eIF2α with the specific phosphatase inhibitor Sal 003 elevated BACE1 levels in 6-month-old 5XFAD mouse brains.
“This idea is strongly supported by our observation that directly raising levels of phospho-eIF2α with the specific phosphatase inhibitor Sal 003 elevated BACE1 levels in 6-month-old 5XFAD mouse brains.”
Quote in the paperSubstantial claim - Premisecitation
Phospho-eIF2α is a critical mediator of the post-transcriptional BACE1 upregulation in sporadic AD and 5XFAD mouse brains.
“phospho-eIF2α is demonstrated to be a critical mediator of the post-transcriptional BACE1 upregulation in sporadic AD and 5XFAD mouse brains [33].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [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
Not checked in the free run.
- Interpretationreasoning
If disease progresses into the more profound stage with BACE1 elevation, deleting a single BACE1 allele is not sufficient to block the BACE1-elevating mechanisms.
“if disease progresses into the more profound stage with BACE1 elevation, deleting a single BACE1 allele is not sufficient to block the BACE1-elevating mechanisms.”
Quote in the paperSubstantial claim - Interpretationown data
Ablation of a single BACE1 allele is not sufficient to prevent BACE1-elevating mechanisms, thus maintaining wild-type levels of BACE1 in BACE1+/−·5XFAD mice at 15-18 months of age.
“These data suggest that the ablation of a single BACE1 allele is not sufficient to prevent BACE1-elevating mechanisms, thus maintaining wild-type levels of this enzyme (i.e., twice the gene copy number) in BACE1+/−·5XFAD mice at 15–18 months of age.”
Quote in the paperSubstantial claim - Premisecitation
Elevations in BACE1 levels, approximately 2-fold, occur in brains of 5XFAD mice as amyloid pathology progresses.
“elevations in BACE1 levels (∼2-fold) have been demonstrated to occur in brains of 5XFAD mice as amyloid pathology progresses [9], [21], [26].”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [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 in the free run.
- cites [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 in the free run.
- cites [26] Zhao J Fu Y Yasvoina M Shao P Hitt B 2007 β-Site amyloid precursor protein cleaving enzyme 1 levels become elevated in neurons around amyloid plaques: implications for Alzheimer's disease pathogenesis. J Neurosci 27 3639 3649 17409228 PMC6672403
Not checked in the free run.
- Interpretationreasoning
The preserved elevation of BACE1 allows continued acceleration of β-cleavage of APP in BACE1+/−·5XFAD mice, which would weaken the abilities of partial BACE1 reduction to suppress Aβ accumulation in brain and improve memory during the advanced phase of disease progression.
“The preserved elevation of BACE1 allows the continued acceleration of β-cleavage of APP in BACE1+/−·5XFAD mice, which would weaken the abilities of partial BACE1 reduction to suppress Aβ accumulation in brain and improve memory during the advanced phase of disease progression.”
Quote in the paperSubstantial claim - Interpretationreasoning
BACE1 levels represent a key factor to determine the degree of Aβ-dependent deterioration of memory performance in the 5XFAD mouse model.
“it seems reasonable to conceive that BACE1 levels represent a key factor to determine the degree of Aβ-dependent deterioration of memory performance in the 5XFAD mouse model.”
Quote in the paperSubstantial claim - Interpretationown data
The efficacies of BACE1+/− deletion in reducing Aβ and C99 accumulation and rescuing cholinergic neurodegeneration and memory deficits become smaller or disappear as disease progresses into the more severe stage with marked elevations in phospho-eIF2α and BACE1 levels in 5XFAD mice.
“Our results clearly indicate that the efficacies of BACE1+/− deletion in reducing Aβ and C99 accumulation and rescuing cholinergic neurodegeneration and memory deficits become smaller or disappear as disease progresses into the more severe stage with marked elevations in phospho-eIF2α and BACE1 levels in 5XFAD mice.”
Quote in the paperSubstantial claim- Rests on an assumption: Approximately 50% BACE1 suppression is likely efficacious.
- Interpretationown data
BACE1 is a direct translational target of the activated phospho-eIF2α pathway in the 5XFAD mouse model of AD.
“demonstrating that BACE1 is a direct translational target of the activated phospho-eIF2α pathway in the 5XFAD mouse model of AD.”
Quote in the paperSubstantial claim - Interpretationown data
Highly increased levels of phospho-eIF2α may account for the preserved elevation of BACE1 in older BACE1+/−·5XFAD mice.
“Therefore, it is conceivable that the highly increased levels of phospho-eIF2α may account for the preserved elevation of BACE1, which corresponds to wild-type levels (i.e., twice the gene copy number), in the older BACE1+/−·5XFAD mice.”
Quote in the paperSubstantial claim - Interpretationown data
These results indicate a dissociation between C99 and BACE1 levels in the older BACE1+/−·5XFAD mouse brains.
“These results indicate a dissociation between C99 and BACE1 levels in the older BACE1+/−·5XFAD mouse brains.”
Quote in the paperSubstantial claim - Interpretationown data
Persistent upregulation of BACE1 through greater phosphorylation of eIF2α can limit the abilities of partial BACE1 reduction to suppress Aβ accumulation in 5XFAD mouse brains during disease progression.
“and that the persistent upregulation of BACE1 through the greater phosphorylation of eIF2α can limit the abilities of partial BACE1 reduction to suppress Aβ accumulation in 5XFAD mouse brains during the course of disease progression.”
Quote in the paperSubstantial claim - Interpretationown data
Merely overexpressing multiple FAD mutant forms of APP is unlikely to cause cholinergic or cognitive defects in 5XFAD mice.
“suggesting that merely overexpressing multiple FAD mutant forms of APP is unlikely to cause cholinergic or cognitive defects in 5XFAD mice.”
Quote in the paperSubstantial claim - Interpretationown data
Partial suppression of BACE1 is effective in preventing cholinergic neurodegeneration associated with AD.
“The results not only provide the first demonstration that partial suppression of BACE1 is effective in preventing cholinergic neurodegeneration associated with AD”
Quote in the paperSubstantial claim - Interpretationreasoning
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.
“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.”
Quote in the paperSubstantial claim- Rests on an assumption: C99 is a direct β-cleavage metabolite of APP.
- Interpretationreasoning
Genetic reductions of BACE1, and consequently of Aβ/C99, can exert beneficial effects in the relatively earlier phases of 5XFAD model possibly by protecting the cholinergic-glutamatergic functional interactions during learning and memory processing in the hippocampal circuitry.
“Therefore, it is interesting to argue that genetic reductions of BACE1, and consequently of Aβ/C99, can exert beneficial effects in the relatively earlier phases of 5XFAD model possibly by protecting the cholinergic-glutamatergic functional interactions during learning and memory processing in the hippocampal circuitry.”
Quote in the paperSubstantial claim - Interpretationreasoning
This mechanism (phospho-eIF2α-driven BACE1 upregulation) is likely to contribute to dampening and eventually abolishing the beneficial effects of BACE1+/− deletion against memory deficits.
“This mechanism is likely to contribute to dampening and eventually abolishing the beneficial effects of BACE1+/− deletion against memory deficits.”
Quote in the paperSubstantial claim - Interpretationown data
The rise in phospho-eIF2α underlies the age-dependent increase in BACE1 in 5XFAD mice.
“Taken together, these results indicate that the rise in phospho-eIF2α underlies the age-dependent increase in BACE1 in 5XFAD mice”
Quote in the paperSubstantial claim - Premisecitation
A growing body of in vitro and in vivo evidence demonstrates physiological roles of the septohippocampal cholinergic inputs in positively modulating various forms of long-lasting synaptic enhancement at CA1 glutamatergic pathways.
“A growing body of in vitro and in vivo evidence demonstrates physiological roles of the septohippocampal cholinergic inputs in positively modulating various forms of long-lasting synaptic enhancement at CA1 glutamatergic pathways [55], [56], [57], [58].”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [55] Fernandez de Sevilla D Nunez A Borde M Malinow R Buno W 2008 Cholinergic-mediated IP3-receptor activation induces long-lasting synaptic enhancement in CA1 pyramidal neurons. J Neurosci 28 1469 1478 18256268 PMC6671582
Not checked in the free run.
- cites [56] Ovsepian SV Anwyl R Rowan MJ 2004 Endogenous acetylcholine lowers the threshold for long-term potentiation induction in the CA1 area through muscarinic receptor activation: in vivo study. Eur J Neurosci 20 1267 1275 15341598
Not checked in the free run.
- cites [57] Sanchez G Alvares Lde O Oberholzer MV Genro B Quillfeldt J 2009 M4 muscarinic receptors are involved in modulation of neurotransmission at synapses of Schaffer collaterals on CA1 hippocampal neurons in rats. J Neurosci Res 87 691 700 18816796
Not checked in the free run.
- Premisecitation
Central lowering of Aβ levels following systemic administration of future BACE1 inhibitor drugs may be limited.
“central lowering of Aβ levels following systemic administration of future BACE1 inhibitor drugs may be limited [16], [17]”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [16] Hussain I Hawkins J Harrison D Hille C Wayne G 2007 Oral administration of a potent and selective non-peptidic BACE-1 inhibitor decreases β-cleavage of amyloid precursor protein and amyloid-β production in vivo. J Neurochem 100 802 809 17156133
Not checked in the free run.
- cites [17] Sankaranarayanan S Holahan MA Colussi D Crouthamel MC Devanarayan V 2009 First demonstration of cerebrospinal fluid and plasma Aβ lowering with oral administration of a β-site amyloid precursor protein-cleaving enzyme 1 inhibitor in nonhuman primates. J Pharmacol Exp Ther 328 131 140 18854490
Not checked in the free run.
- Interpretationown data
The same degree of β-secretase suppression (e.g., 50% by BACE1+/− deletion) becomes less efficacious and eventually ineffective in reducing Aβ/C99 accumulation and rescuing cholinergic neurodegeneration or memory deficits in 5XFAD mice as disease progresses into the more profound stage that is accompanied by BACE1 upregulation.
“In conclusion, the results presented here demonstrate that the same degree of β-secretase suppression (e.g., 50% by BACE1+/− deletion) becomes less efficacious and eventually ineffective in reducing Aβ/C99 accumulation and rescuing cholinergic neurodegeneration or memory deficits in 5XFAD mice as disease progresses into the more profound stage that is accompanied by BACE1 upregulation.”
Quote in the paperSubstantial claim - Interpretationreasoning
Failure of BACE1+/− deletion to rescue memory deficits in 5XFAD mice at the advanced phase may be attributable to high residual levels of neurotoxic C99 fragments in addition to Aβ42 peptides in brain.
“Therefore, it seems plausible that failure of BACE1+/− deletion to rescue memory deficits in 5XFAD mice at the advanced phase may be attributable to the high residual levels of neurotoxic C99 fragments in addition to Aβ42 peptides in brain.”
Quote in the paperSubstantial claim
- May combine two claims. 18
- Classified as probably not a substantial claim. 12
May combine two claims.
Findingown dataAt 6 months of age, the 5XFAD-associated increase in phospho-eIF2α level is marginal and is completely abolished in BACE1+/−·5XFAD mice.
“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)”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataBACE1+/− deletion fails to improve the spatial working memory defect in 5XFAD mice at 15-18 months of age, with no significant difference in alternation between 5XFAD and BACE1+/−·5XFAD mice.
“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.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe number of ChAT-immunoreactive neurons in 5XFAD and BACE1+/−·5XFAD mice at 15-18 months of age is significantly lower than that of wild-type control mice and is indistinguishable between the two groups.
“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).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataBACE1+/− deletion significantly suppresses β-cleavage of APP in 5XFAD mice at 6 months of age, reducing C99 and Aβ42 levels by approximately 53% and 67%, respectively.
“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)”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataBACE1+/− deletion restored the cholinergic defects to normal consistent with improvements in hippocampal spatial memory function in 5XFAD mice at 6 months of age.
“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.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataHeterozygous BACE1 knockout reduced BACE1 expression by ~50% in 15-18-month-old 5XFAD mice, but their C99 levels were not significantly lower than age-matched 5XFAD levels.
“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.”
Quote in the paperSubstantial claimMay combine two claims.
Premisecitation5XFAD 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.
“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].”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [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 in the free run.
- cites [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 in the free run.
- cites [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
Not checked in the free run.
Probably not a substantial claim: may not pass S2 (checkable).
PremisecitationBACE1 represents an excellent therapeutic target for the treatment of AD.
“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].”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [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 in the free run.
- cites [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 in the free run.
- cites [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 in the free run.
Classified as probably not a substantial claim. May combine two claims.
PremisecitationPartial reduction of BACE1 suffices to attenuate Aβ-related pathology and rescue synaptic and memory deficits in mouse models of AD.
“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].”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [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 in the free run.
- cites [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 in the free run.
- cites [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
Not checked in the free run.
May combine two claims.
PremisecitationBACE1 expression and activity levels are significantly elevated in sporadic AD brains, which is considered a crucial contributing factor in the pathogenesis of AD.
“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].”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [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 in the free run.
- cites [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 in the free run.
- cites [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
Not checked in the free run.
Classified as probably not a substantial claim.
PremisecitationThe effects of BACE1+/− deletion in reducing total Aβ levels and plaque load in PDAPP transgenic mice become smaller during the course of disease progression.
“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]”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [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
Not checked in the free run.
May combine two claims.
PremisecitationComplete deletion of BACE1 (BACE1−/−) can still rescue impaired spontaneous alternation performance concomitant with prevention of Aβ deposition and neuronal loss in 5XFAD mice at advanced age.
“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].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [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 in the free run.
Classified as probably not a substantial claim.
PremisecitationSpontaneous alternation in the Y-maze represents a measure of spatial working memory.
“spontaneous alternation in the Y-maze that represents a measure of spatial working memory [34]”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [34] Lalonde R 2002 The neurobiological basis of spontaneous alternation. Neurosci Biobehav Rev 26 91 104 11835987
Not checked in the free run.
Classified as probably not a substantial claim.
PremisecitationPhosphorylation of eIF2α plays an important role in mediating the post-transcriptional upregulation of BACE1 in human AD and 5XFAD mouse brains.
“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].”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [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 in the free run.
- cites [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
Not checked in the free run.
May combine two claims.
Interpretationown dataPartial 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.
“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.”
Quote in the paperSubstantial claim- Rests on an assumption: Approximately 50% BACE1 suppression is likely efficacious.
Classified as probably not a substantial claim. May combine two claims.
PremisecitationGenetic deletion of BACE1 prevents AD-like pathologies and improves cognitive impairments in different transgenic mouse models.
“genetic deletion of BACE1 prevents AD-like pathologies and improves cognitive impairments in different transgenic mouse models [7], [8], [9], [10].”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [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 in the free run.
- cites [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 in the free run.
- cites [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 in the free run.
Classified as probably not a substantial claim.
PremisecitationBACE1 is responsible for initiating the production of Aβ.
“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].”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [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 in the free run.
- cites [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 in the free run.
- cites [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 in the free run.
Classified as probably not a substantial claim.
PremisecitationThe septohippocampal cholinergic pathway has an established role in mediating spatial working memory including spontaneous alternation performance in the Y-maze.
“The septohippocampal cholinergic pathway has an established role in mediating spatial working memory including spontaneous alternation performance in the Y-maze [35], [36], [37].”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [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 in the free run.
- cites [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 in the free run.
- cites [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
Not checked in the free run.
May combine two claims.
PremisecitationAt ≥9 months of age, 5XFAD mice show severe memory deficits together with further developed Aβ pathology and marked synaptic degeneration and neuronal loss.
“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].”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [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 in the free run.
- cites [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 in the free run.
- cites [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 in the free run.
May combine two claims.
Interpretationown dataPotential mechanism-based side effects might occur only in completely abolishing BACE1 activity but not in partially inhibiting it.
“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.”
Quote in the paperSubstantial claim- Rests on an assumption: These phenotypes (liabilities of complete BACE1 deletion) are not observed in BACE1+/− knockout mice.
May combine two claims.
PremisecitationRecent studies reveal some liabilities of complete BACE1 deletion including hypomyelination and altered synaptic functions or neuronal activities.
“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].”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [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 in the free run.
- cites [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 in the free run.
- cites [6] Cole SL Vassar R 2007 The Alzheimer's disease β-secretase enzyme, BACE1. Mol Neurodegener 2 22 18005427 PMC2211305
Not checked in the free run.
Classified as probably not a substantial claim.
PremisecitationAccumulation of the amyloid-β peptide plays a central role in triggering a pathogenic cascade ultimately leading to neuronal death and profound memory deficits.
“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].”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [1] Hardy JA Higgins GA 1992 Alzheimer's disease: the amyloid cascade hypothesis. Science 256 184 185 1566067
Not checked in the free run.
- cites [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
Not checked in the free run.
May combine two claims.
InterpretationreasoningNeurotoxic Aβ42 and/or C99 species are responsible for killing cholinergic neurons.
“but also indicate that neurotoxic Aβ42 and/or C99 species are responsible for killing cholinergic neurons.”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationreasoningPhosphorylation 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.
“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.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
PremisecitationTransgenic overexpression or central administration of potentially amyloidogenic C99 fragments has been reported to induce memory defects and neurodegeneration.
“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].”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [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 in the free run.
- cites [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 in the free run.
- cites [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
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenAll experiments were done blind with respect to the genotype of the mice at 6 and 15-18 months of age.
“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).”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationSeveral 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.
“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];”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [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 in the free run.
- cites [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 in the free run.
- cites [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
Not checked in the free run.
May combine two claims.
InterpretationreasoningThe 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.
“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.”
Quote in the paperSubstantial claim
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?
Significant memory impairment is observed in 5XFAD mice before six months of age.
“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.
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The mouse brain in stereotaxic coordinates
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“Mice were transcardially perfused with 4% paraformaldehyde in phosphate buffered saline (PBS) under deep isoflurane anesthesia. The brain was removed and sectioned coronally at 40 µm on a vibratome (VT1200, Leica Microsystems), and successive sections were stored in PBS containing 0.01% sodium azide at 4°C. Four secti…”
MethodInfluentialThe Amyloid Hypothesis of Alzheimer’s Disease: Progress and Problems on the Road to Therapeutics
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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].”
BackgroundOakley, H., Cole, S. L., Logan, S., Maus, E., Shao, P., Craft, J., Guillozet-Bongaarts, A., Ohno, M., Disterhoft, J., Van Eldik, L., et al. (2006) · The Journal of Neuroscience · doi:10.1523/jneurosci.1202-06.2006 · Cited by 3,530 · see citing works
Self-citationHébert, S. S., Horré, K., Nicolaï, L., Papadopoulou, A. S., Mandemakers, W., Silahtaroglu, A. N., Kauppinen, S., Delacourte, A., & De Strooper, B. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0710263105 · Cited by 1,183 · see citing works
The neurobiological basis of spontaneous alternation
Lalonde, R. (2002) · Neuroscience & Biobehavioral Reviews · doi:10.1016/s0149-7634(01)00041-0 · Cited by 842 · cited 1× · see citing works
“represents a measure of spatial working memory [34] (Fig.”
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The secretases: enzymes with therapeutic potential in Alzheimer disease
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BACE1 is the major β-secretase for generation of Aβ peptides by neurons
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Elevated β-secretase expression and enzymatic activity detected in sporadic Alzheimer disease
Yang, L.-B., Lindholm, K., Yan, R., Citron, M., Xia, W., Yang, X.-L., Beach, T., Sue, L., Wong, P., Price, D., et al. (2003) · Nature Medicine · doi:10.1038/nm0103-3 · Cited by 729 · see citing works
β-Secretase Protein and Activity Are Increased in the Neocortex in Alzheimer Disease
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“memory declines on hippocampus-dependent tasks between 4–6 months with moderate Ab accumulation [8,28,29,30,31].”
BackgroundThe Alzheimer's disease Beta-secretase enzyme, BACE1
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“Meanwhile, the percent alternation was indistinguishable between BACE1 and wild-type mice at 6 or 15–18 months of age, demonstrating that BACE1 mice were normal in spatial working memory function in contrast to BACE1 mice that exhibited poor spontaneous alternation performance in the Ymaze in our previous studies [7,9…”
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O’Connor, T., Sadleir, K. R., Maus, E., Velliquette, R. A., Zhao, J., Cole, S. L., Eimer, W. A., Hitt, B. D., Bembinster, L. A., Lammich, S., et al. (2008) · Neuron · doi:10.1016/j.neuron.2008.10.047 · Cited by 422 · see citing works
Targeting BACE1 with siRNAs ameliorates Alzheimer disease neuropathology in a transgenic model
Singer, O., Marr, R. A., Rockenstein, E. M., Crews, L. A., Coufal, N. G., Gage, F. H., Verma, I. M., & Masliah, E. (2005) · Nature Neuroscience · doi:10.1038/nn1531 · Cited by 420 · cited 1× · see citing works
“Emerging evidence suggests that partial reduction of BACE1, which is induced by BACE1 gene deletion [21,22], siRNA targeting BACE1 [18] and immunization with BACE1 ectodomain [19], can diminish brain Ab levels and amyloid-related”
BackgroundZhao, J., Fu, Y., Yasvoina, M., Shao, P., Hitt, B., O'Connor, T., Logan, S., Maus, E., Citron, M., Berry, R., et al. (2007) · The Journal of Neuroscience · doi:10.1523/jneurosci.4396-06.2007 · Cited by 365 · see citing works
Depletion of GGA3 Stabilizes BACE and Enhances β-Secretase Activity
Tesco, G., Koh, Y. H., Kang, E. L., Cameron, A. N., Das, S., Sena-Esteves, M., Hiltunen, M., Yang, S.-H., Zhong, Z., Shen, Y., et al. (2007) · Neuron · doi:10.1016/j.neuron.2007.05.012 · Cited by 337 · see citing works
Nalbantoglu, J. N., Santiago, G. T., Lahsaïni, A., Poirier, J., Goncalves, O., Verge, G. M., Momoli, F., Welner, S. A., Massicotte, G., Julien, J., et al. (1997) · Nature · doi:10.1038/387500a0 · Cited by 334 · cited 1× · see citing works
“induce memory defects and neurodegeneration [45,46,47,48,49].”
Kimura, R., & Ohno, M. (2009) · Neurobiology of Disease · doi:10.1016/j.nbd.2008.10.006 · Cited by 333 · cited 2× · see citing works
“memory declines on hippocampus-dependent tasks between 4–6 months with moderate Ab accumulation [8,28,29,30,31].”
BackgroundSelf-citationMcConlogue, L., Buttini, M., Anderson, J. P., Brigham, E. F., Chen, K. S., Freedman, S. B., Games, D., Johnson-Wood, K., Lee, M., Zeller, M., et al. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m611687200 · Cited by 300 · cited 1× · see citing works
“the course of disease progression [20]; however, the underlying”
BackgroundTemporal memory deficits in Alzheimer’s mouse models: Rescue by genetic deletion of BACE1
Ohno, M., Chang, L., Tseng, W., Oakley, H., Citron, M., Klein, W. L., Vassar, R., & Disterhoft, J. F. (2006) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2005.04551.x · Cited by 298 · cited 2× · see citing works
“memory declines on hippocampus-dependent tasks between 4–6 months with moderate Ab accumulation [8,28,29,30,31].”
BackgroundMethodSelf-citationBACE1 gene deletion prevents neuron loss and memory deficits in 5XFAD APP/PS1 transgenic mice
Ohno, M., Cole, S. L., Yasvoina, M., Zhao, J., Citron, M., Berry, R., Disterhoft, J. F., & Vassar, R. (2007) · Neurobiology of Disease · doi:10.1016/j.nbd.2006.12.008 · Cited by 290 · cited 4× · see citing works
“Meanwhile, the percent alternation was indistinguishable between BACE1 and wild-type mice at 6 or 15–18 months of age, demonstrating that BACE1 mice were normal in spatial working memory function in contrast to BACE1 mice that exhibited poor spontaneous alternation performance in the Ymaze in our previous studies [7,9…”
BackgroundResultInfluentialSelf-citationChang, R. C. C., Wong, A. K. Y., Ng, H.-K., & Hugon, J. (2002) · NeuroReport · doi:10.1097/00001756-200212200-00011 · Cited by 289 · cited 1× · see citing works
“. Furthermore, 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”
BackgroundShinoe, T., Matsui, M., Taketo, M. M., & Manabe, T. (2005) · Journal of Neuroscience · doi:10.1523/jneurosci.2338-05.2005 · Cited by 237 · cited 1× · see citing works
“A growing body of in vitro and in vivo evidence demonstrates physiological roles of the septohippocampal cholinergic inputs in positively modulating various forms of long-lasting synaptic enhancement at CA1 glutamatergic pathways [55,56,57,58].”
BackgroundTranscriptional Regulation of β-Secretase by p25/cdk5 Leads to Enhanced Amyloidogenic Processing
Wen, Y., Yu, W. H., Maloney, B., Bailey, J. A., Ma, J., Marié, I., Maurin, T., Wang, L., Figueroa, H. Y., Herman, M., et al. (2008) · Neuron · doi:10.1016/j.neuron.2008.02.024 · Cited by 201 · see citing works
Hussain, I., Hawkins, J., Harrison, D. C., Hille, C. J., Wayne, G. J., Cutler, L., Buck, T., Walter, D. S., Demont, E. H., Howes, C., et al. (2006) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2006.04260.x · Cited by 197 · cited 1× · see citing works
“. In particular, the larger active site of BACE1 renders it extremely difficult to inhibit this aspartic protease with small-molecule compounds that can pass the blood-brain barrier. Given that central lowering of Aβ levels following systemic administration of future BACE1 inhibitor drugs may be limited”
Backgroundp25/Cyclin-Dependent Kinase 5 Induces Production and Intraneuronal Accumulation of Amyloid βIn Vivo
Cruz, J. C., Kim, D., Moy, L. Y., Dobbin, M. M., Sun, X., Bronson, R. T., & Tsai, L. (2006) · Journal of Neuroscience · doi:10.1523/jneurosci.3133-06.2006 · Cited by 197 · see citing works
β-Secretase inhibition for the treatment of Alzheimer's disease – promise and challenge
Citron, M. (2004) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2003.12.004 · Cited by 194 · see citing works
β-Secretase as a Therapeutic Target for Alzheimer’s Disease
Ghosh, A., Gemma, S., & Tang, J. J. N. (2008) · Neurotherapeutics · doi:10.1016/j.nurt.2008.05.007 · Cited by 175 · see citing works
Cholinergic Changes in the APP23 Transgenic Mouse Model of Cerebral Amyloidosis
Boncristiano, S., Calhoun, M. E., Kelly, P. H., Pfeifer, M., Bondolfi, L., Stalder, M., Phinney, A. L., Abramowski, D., Sturchler-Pierrat, C., Enz, A., et al. (2002) · The Journal of Neuroscience · doi:10.1523/jneurosci.22-08-03234.2002 · Cited by 160 · cited 1× · see citing works
“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 [51,5…”
BackgroundOvsepian, S. V., Anwyl, R., & Rowan, M. J. (2004) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2004.03582.x · Cited by 153 · cited 1× · see citing works
“A growing body of in vitro and in vivo evidence demonstrates physiological roles of the septohippocampal cholinergic inputs in positively modulating various forms of long-lasting synaptic enhancement at CA1 glutamatergic pathways [55,56,57,58].”
Backgroundde Sevilla, D. F., Núñez, Á., Borde, M., Malinow, R., & Buño, W. (2008) · Journal of Neuroscience · doi:10.1523/jneurosci.2723-07.2008 · Cited by 143 · cited 1× · see citing works
“A growing body of in vitro and in vivo evidence demonstrates physiological roles of the septohippocampal cholinergic inputs in positively modulating various forms of long-lasting synaptic enhancement at CA1 glutamatergic pathways [55,56,57,58].”
BackgroundKimura, R., Devi, L., & Ohno, M. (2010) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2010.06608.x · Cited by 139 · cited 4× · see citing works
“Emerging evidence suggests that partial reduction of BACE1, which is induced by BACE1 gene deletion [21,22], siRNA targeting BACE1 [18] and immunization with BACE1 ectodomain [19], can diminish brain Ab levels and amyloid-related”
BackgroundMethodInfluentialSelf-citationCholinergic dysfunction, neuronal damage and axonal loss in TgCRND8 mice
Bellucci, A., Luccarini, I., Scali, C., Prosperi, C., Giovannini, M. G., Pepeu, G., & Casamenti, F. (2006) · Neurobiology of Disease · doi:10.1016/j.nbd.2006.03.012 · Cited by 130 · cited 1× · see citing works
“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 [51,5…”
BackgroundBACE1 and BACE2 enzymatic activities in Alzheimer’s disease
Ahmed, R. R., Holler, C. J., Webb, R. L., Li, F., Beckett, T. L., & Murphy, M. P. (2009) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2009.06528.x · Cited by 127 · see citing works
Zhang, X., Cai, Y., Xiong, K., Cai, H., Luo, X., Feng, J., Clough, R. W., Struble, R. G., Patrylo, P. R., & Yan, X. (2009) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2009.07017.x · Cited by 117 · see citing works
Sankaranarayanan, S., Holahan, M. A., Colussi, D. J., Crouthamel, M., Devanarayan, V., Ellis, J. D., Espeseth, A. S., Gates, A. T., Graham, S. L., Gregro, A. R., et al. (2008) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.108.143628 · Cited by 107 · see citing works
Towards Disease-Modifying Treatment of Alzheimers Disease: Drugs Targeting β -Amyloid
Frisardi, V., Solfrizzi, V., Imbimbo, B. P., Capurso, C. A., D’Introno, A., Colacicco, A. M., Vendemiale, G., Seripa, D., Pilotto, A., Capurso, C. A., et al. (2010) · Current Alzheimer Research · doi:10.2174/156720510790274400 · Cited by 107 · see citing works
Cholinergic forebrain degeneration in the APPswe/PS1ΔE9 transgenic mouse
Perez, S. E., Dar, S., Ikonomović, M. D., DeKosky, S. T., & Mufson, E. J. (2007) · Neurobiology of Disease · doi:10.1016/j.nbd.2007.06.015 · Cited by 97 · see citing works
Failures to reconsolidate memory in a mouse model of Alzheimer’s disease
Ohno, M. (2009) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2009.05.001 · Cited by 95 · cited 1× · see citing works
“memory declines on hippocampus-dependent tasks between 4–6 months with moderate Ab accumulation [8,28,29,30,31].”
BackgroundSelf-citationOhno, M., Yamamoto, T. T., & Watanabe, S. (1992) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(25)10500-4 · Cited by 93 · cited 10× · see citing works
“Spontaneous alternation Y-maze test Spontaneous alternation performance was tested using a symmetrical Y-maze, as described previously [7,22].”
InfluentialSelf-citationBerger-Sweeney, J. E., McPhie, D. L., Arters, J., Greenan, J., Oster‐Granite, M. L., & Neve, R. L. (1999) · Molecular Brain Research · doi:10.1016/s0169-328x(99)00014-5 · Cited by 91 · cited 1× · see citing works
“induce memory defects and neurodegeneration [45,46,47,48,49].”
Chang, Q., & Gold, P. E. (2004) · Hippocampus · doi:10.1002/hipo.10160 · Cited by 89 · cited 10× · see citing works
“Spontaneous alternation Y-maze test Spontaneous alternation performance was tested using a symmetrical Y-maze, as described previously [7,22].”
InfluentialChristensen, D. Z., Bayer, T. A., & Wirths, O. (2010) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2008.07.022 · Cited by 77 · see citing works
Cell biology, regulation and inhibition of β‐secretase (BACE‐1)
Hunt, C. E., & Turner, A. J. (2009) · FEBS Journal · doi:10.1111/j.1742-4658.2009.06929.x · Cited by 73 · see citing works
Devi, L., & Ohno, M. (2009) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2009.07031.x · Cited by 67 · see citing works
Self-citationSarajärvi, T., Haapasalo, A., Viswanathan, J., Mäkinen, P. M., Laitinen, M. H., Soininen, H. S., & Hiltunen, M. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.036202 · Cited by 64 · cited 1× · see citing works
“of BACE1 [38,39], increased phosphorylation of the translation initiation factor eIF2a [33], transcriptional upregulation mediated”
BackgroundContestabile, A., Ciani, E., & Contestabile, A. (2007) · Neurochemical Research · doi:10.1007/s11064-007-9497-4 · Cited by 62 · cited 1× · see citing works
“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 [51,5…”
BackgroundSong, D. ‐., Won, M., Jung, J.-S., Lee, J.-S., Kang, T., Suh, H., Huh, S., Paek, S. H., Kim, Y. ‐., Kim, S. H., et al. (1998) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.1998.71020875.x · Cited by 60 · see citing works
Human β-secretase (BACE) and BACE Inhibitors: Progress Report
John, V. (2006) · Current Topics in Medicinal Chemistry · doi:10.2174/156802606776743084 · Cited by 56 · cited 1× · see citing works
“. However, since the discovery of BACE1, medicinal chemistry toward the development of efficacious inhibitors has proved to be a challenging task”
BackgroundLee, K.-W., Im, J., Song, J.-S., Lee, S. H., Lee, H.-J., Ha, H.-Y., Koh, J., Gwag, B. J., Yang, S.-D., Paik, S., et al. (2005) · Neurobiology of Disease · doi:10.1016/j.nbd.2005.09.011 · Cited by 48 · cited 1× · see citing works
“induce memory defects and neurodegeneration [45,46,47,48,49].”
Choi, S. H., Park, C. H., Koo, J. W., Seo, J., Kim, H., Jeong, S., Lee, J., Kim, S. S., & Suh, Y. (2001) · The FASEB Journal · doi:10.1096/fj.00-0859fje · Cited by 47 · see citing works
Amyloid‐beta reduction by memapsin 2 (beta‐secretase) immunization
Chang, W., Downs, D., Huang, X., Da, H., Fung, K.-M. A., & Tang, J. (2007) · The FASEB Journal · doi:10.1096/fj.06-7993com · Cited by 40 · see citing works
Ohno, M. (2006) · Reviews in the Neurosciences · doi:10.1515/revneuro.2006.17.4.429 · Cited by 32 · see citing works
Self-citationSanchez, G. M., Alvares, L. D. O., Oberholzer, M. V., Genro, B. P., Quillfeldt, J. A., da Costa, J. C., Červeñanský, C., Jerusalinsky, D. A., & Kornisiuk, E. E. (2008) · Journal of Neuroscience Research · doi:10.1002/jnr.21876 · Cited by 28 · see citing works
Feasey‐Truger, K. J., Li, B.-H., & ten Bruggencate, G. (1992) · Brain Research · doi:10.1016/0006-8993(92)91711-m · Cited by 24 · see citing works
篠江, 徹. (2006) · Medical Entomology and Zoology · Cited by 17 · see citing works
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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 · see citing works
Devi, L., & Ohno, M. (2012) · Neuropsychopharmacology · doi:10.1038/npp.2011.191 · Cited by 282 · see citing works
“…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
Bilkei‐Gorzó, A. (2013) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2013.12.009 · Cited by 244 · see citing works
Kocahan, S., & Doğan, Z. (2017) · Clinical Psychopharmacology and Neuroscience · doi:10.9758/cpn.2017.15.1.1 · Cited by 238 · see citing works
Aβ reduction in BACE1 heterozygous null 5XFAD mice is associated with transgenic APP level
Sadleir, K. R., Eimer, W. A., Cole, S. L., & Vassar, R. (2015) · Molecular Neurodegeneration · doi:10.1186/1750-1326-10-1 · Cited by 213 · see citing works
“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].”
BackgroundResultInfluentialZhu, Z., Yan, J., Jiang, W., Yao, X., Chen, J., Chen, L., Li, C., Hu, L., Jiang, H., & Shen, X. (2013) · Journal of Neuroscience · doi:10.1523/jneurosci.4790-12.2013 · Cited by 207 · see citing works
“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 202 · see citing works
“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 · see citing works
“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 · see citing works
Landel, V., Baranger, K., Virard, I., Loriod, B., Khrestchatisky, M., Rivera, S., Benech, P., & Féron, F. (2014) · Molecular Neurodegeneration · doi:10.1186/1750-1326-9-33 · Cited by 176 · see citing works
Devi, L., & Ohno, M. (2014) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2014.04.031 · Cited by 169 · see citing works
“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).”
InfluentialSelf-citationKosel, F., Pelley, J. M. S., & Franklin, T. B. (2020) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2020.02.012 · Cited by 162 · see citing works
Activation of mTOR: a culprit of Alzheimer&rsquo;s disease?
Cai, Z., Zhou, Y., Xiao, M., Yan, L.-J., & He, W. (2015) · Neuropsychiatric Disease and Treatment · doi:10.2147/ndt.s75717 · Cited by 161 · see citing works
Devi, L., Alldred, M. J., Ginsberg, S. D., & Ohno, M. (2012) · PLoS ONE · doi:10.1371/journal.pone.0032792 · Cited by 155 · see citing works
Self-citationGupta, V., You, Y., Li, J., Gupta, V. B., Golzan, M., Klistorner, A. I., van den Buuse, M., & Graham, S. L. (2014) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2014.05.026 · Cited by 149 · see citing works
“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 142 · see citing works
Lin, Y., Jin, J., Lv, R., Luo, Y. M., Dai, W.-P., Li, W., Tang, Y., Wang, Y., Ye, X., & Lin, W. (2021) · Acta Neuropathologica Communications · doi:10.1186/s40478-021-01198-3 · Cited by 138 · see citing works
“The 5xFAD mice develop aggressive amyloid pathology and showed cognitive deficits across multiple domains around 4–5 months of age [18, 24, 36, 52].”
BackgroundDevi, L., & Ohno, M. (2011) · Neurobiology of Disease · doi:10.1016/j.nbd.2011.09.001 · Cited by 121 · see citing works
“…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).”
Self-citationSpines, plasticity, and cognition in Alzheimer's model mice
Spires-Jones, T., & Knafo, S. (2012) · Neural Plasticity · doi:10.1155/2012/319836 · Cited by 133 · see citing works
“6–12 Impaired [144] Impaired [102, 103] Impaired [82, 144, 145]”
BackgroundTransgenic Mouse Models of Alzheimer’s Disease: An Integrative Analysis
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 130 · see citing works
Devi, L., Alldred, M. J., Ginsberg, S. D., & Ohno, M. (2010) · Molecular Brain · doi:10.1186/1756-6606-3-34 · Cited by 129 · see citing works
“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 121 · see citing works
“…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 120 · see citing works
“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 113 · see citing works
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 · see citing works
“…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 114 · see citing works
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 97 · see citing works
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 · see citing works
Centella Asiatica Improves Memory and Promotes Antioxidative Signaling in 5XFAD Mice
Matthews, D. G., Caruso, M., Murchison, C. F., Zhu, J. Y., Wright, K. M., Harris, C. J., Gray, N. E., Quinn, J. F., & Soumyanath, A. (2019) · Antioxidants · doi:10.3390/antiox8120630 · Cited by 86 · see citing works
“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 88 · see citing works
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 · see citing works
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 · see citing works
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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
Wirths, O., & Zampar, S. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21218144 · Cited by 75 · see citing works
“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
Machlovi, S. I., Neuner, S. M., Hemmer, B. M., Khan, R., Liu, Y., Huang, M., Zhu, J. D., Castellano, J. M., Cai, D., Marcora, E., et al. (2022) · Neurobiology of Disease · doi:10.1016/j.nbd.2022.105615 · Cited by 73 · see citing works
“, 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 71 · see citing works
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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 · see citing works
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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., Pimenova, A. A., Lo, A. C., Ciesielska, M., Lichtenthaler, S., Maeyer, J. D. D., Schuurkes, J., D'Hooge, R., & de Strooper, B. (2013) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2013.01.020 · Cited by 53 · see citing works
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 57 · see citing works
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 · see citing works
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 58 · see citing works
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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 52 · see citing works
“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 49 · see citing works
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 · see citing works
“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 48 · see citing works
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 42 · see citing works
“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 42 · see citing works
Guo, X., Lv, J., Lu, J., Fan, L., Huang, X., Hu, L., Wang, J., & Shen, X. (2017) · Neuropharmacology · doi:10.1016/j.neuropharm.2017.11.033 · Cited by 41 · see citing works
“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 · see citing works
“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 38 · see citing works
“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 · see citing works
“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 39 · see citing works
“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 34 · see citing works
“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 44 · see citing works
Roddick, K. M., Schellinck, H. M., & Brown, R. E. (2014) · Behavioural Brain Research · doi:10.1016/j.bbr.2014.04.038 · Cited by 37 · see citing works
Cheng, N., Cai, H., & Belluscio, L. (2011) · Journal of Neuroscience · doi:10.1523/jneurosci.1714-11.2011 · Cited by 36 · see citing works
Paesler, K., Xie, K., Hettich, M. M., Siwek, M. E., Ryan, D. P., Schröder, S., Papazoglou, A., Broich, K., Müller, R., Trog, A., et al. (2015) · Neural Plasticity · doi:10.1155/2015/825157 · Cited by 36 · see citing works
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 · see citing works
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 31 · see citing works
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 · see citing works
Kim, S., Nam, Y., Jeong, Y.-O., Park, H. H., Lee, S.-K., Shin, S. J., Jung, H., Kim, B., Hong, S. B., Park, Y., et al. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20163992 · Cited by 29 · see citing works
“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 · see citing works
“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 · see citing works
Cholinergic neurodegeneration in Alzheimer disease mouse models
Shekari, A., & Fahnestock, M. L. (2021) · Handbook of clinical neurology · doi:10.1016/b978-0-12-819973-2.00013-7 · Cited by 27 · see citing works
Post-translational regulation of the β-secretase BACE1
Araki, W. (2016) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2016.04.009 · Cited by 28 · see citing works
Devi, L., & Ohno, M. (2015) · Neuroscience · doi:10.1016/j.neuroscience.2015.08.037 · Cited by 26 · see citing works
“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 · see citing works
Does any drug to treat cancer target mTOR and iron hemostasis in neurodegenerative disorders?
Farshbaf, M. J., & Ghaedi, K. (2016) · BioMetals · doi:10.1007/s10534-016-9981-x · Cited by 22 · see citing works
“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 20 · see citing works
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 · see citing works
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Faisal, M., Aid, J., o‘g‘li, N. B. H., Lee, B., & Hickey, M. A. (2023) · PLoS ONE · doi:10.1371/journal.pone.0281003 · Cited by 16 · see citing works
“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 · see citing works
Takuma, K., Mizoguchi, H., Funatsu, Y., et al. (2012) · Neuroscience · doi:10.1016/j.neuroscience.2012.01.034 · Cited by 16 · see citing works
“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 15 · see citing works
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 · see citing works
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 · see citing works
“…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).”
BackgroundHe, K., Li, Y., Xiong, W., et al. (2024) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2024.10.301 · Cited by 13 · see citing works
Guix, F. X., Sartório, C. L., & ILL‐Raga, G. (2019) · Journal of Alzheimer s Disease Reports · doi:10.3233/adr-180089 · Cited by 13 · see citing works
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 · see citing works
Borreca, A., Valeri, F., Luca, M. D., Ernst, L., Russo, A., Nobili, A., Cordella, A., Corsetti, V., Amadoro, G., Mercuri, N. B., et al. (2020) · Neurobiology of Disease · doi:10.1016/j.nbd.2020.104787 · Cited by 11 · see citing works
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 10 · see citing works
“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 · see citing works
“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 · see citing works
“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 · see citing works
Lazarev, V. F., Dutysheva, E. A., Mikhaylova, E. R., et al. (2022) · Molecules · doi:10.3390/molecules27248950 · Cited by 8 · see citing works
“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 7 · see citing works
“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 · see citing works
“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
Reineke, L. C., Zhu, P., Dalwadi, U., Dooling, S. W., Liu, Y., Wang, I.-C., Young-Baird, S. K., Okoh, J. T., Kuncha, S. K., Zhou, H., et al. (2026) · Science · doi:10.1126/science.aea8782 · Cited by 7 · see citing works
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Campbell, K. J., Jiang, P., Olker, C. J., Lin, X., Kim, S. Y., Lee, C., Song, E. J., Turek, F. W., & Vitaterna, M. H. (2024) · Frontiers in Neurology · doi:10.3389/fneur.2024.1430989 · Cited by 6 · see citing works
- 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
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Pharmacology › 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
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