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Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice
Open accessAbstract
β-Site APP-cleaving enzyme 1 (BACE1) initiates amyloid-β (Aβ) generation and thus represents a prime therapeutic target in treating Alzheimer's disease (AD). Notably, increasing evidence indicates that BACE1 levels become elevated in AD brains as disease progresses; however, it remains unclear how the BACE1 upregulation may affect efficacies of therapeutic interventions including BACE1-inhibiting approaches. Here, we crossed heterozygous BACE1 knockout mice with AD transgenic mice (5XFAD model) and compared the abilities of partial BACE1 reduction to rescue AD-like phenotypes at earlier (6-month-old) and advanced (15-18-month-old) stages of disease, which expressed normal (∼100%) and elevated (∼200%) levels of BACE1, respectively. BACE1(+/-) deletion rescued memory deficits as tested by the spontaneous alternation Y-maze task in 5XFAD mice at the earlier stage and prevented their septohippocampal cholinergic deficits associated with significant neuronal loss. Importantly, BACE1(+/-) deletion was no longer able to rescue memory deficits or cholinergic neurodegeneration in 5XFAD mice at the advanced stage. Moreover, BACE1(+/-) deletion significantly reduced levels of Aβ42 and the β-secretase-cleaved C-terminal fragment (C99) in 6-month-old 5XFAD mouse brains, while these neurotoxic β-cleavage products dramatically elevated with age and were not affected by BACE1(+/-) deletion in 15-18-month-old 5XFAD brains. Interestingly, although BACE1(+/-) deletion lowered BACE1 expression by ∼50% in 5XFAD mice irrespective of age in concordance with the reduction in gene copy number, BACE1 equivalent to wild-type controls remained in BACE1(+/-)·5XFAD mice at the advanced age. In accord, phosphorylation of the translation initiation factor eIF2α, an important mediator of BACE1 elevation, was dramatically increased (∼9-fold) in 15-18-month-old 5XFAD mice and remained highly upregulated (∼6-fold) in age-matched BACE1(+/-)·5XFAD mice. Together, our results indicate that partial reduction of BACE1 is not sufficient to block the phospho-eIF2α-dependent BACE1 elevation during the progression of AD, thus limiting its abilities to reduce cerebral Aβ/C99 levels and rescue memory deficits and cholinergic neurodegeneration.
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TL;DR
Partial (heterozygous) BACE1 reduction rescued memory deficits and septohippocampal cholinergic neurodegeneration in 6-month-old 5XFAD mice but failed to do so at 15–18 months, when BACE1 and phospho-eIF2α were elevated. The results suggest that phospho-eIF2α-driven BACE1 elevation limits the efficacy of partial BACE1 suppression as Alzheimer’s-like disease progresses.
Key findings
- BACE1+/− deletion rescued spontaneous alternation Y-maze deficits in 6-month-old 5XFAD mice, but not in 15–18-month-old 5XFAD mice (no significant difference between 5XFAD and BACE1+/−·5XFAD, p = 0.24).
- BACE1+/− deletion restored hippocampal ChAT levels and ChAT-positive Ch1/2 neuron numbers in 6-month-old 5XFAD mice, but not at 15–18 months (ChAT trend p = 0.10; neuron number p = 0.32).
- BACE1+/− deletion reduced C99 by ∼53% and Aβ42 by ∼67% in 6-month-old 5XFAD brains; at 15–18 months, reductions were only ∼18% for C99 and ∼20% for Aβ42 and not significant (p = 0.14 and p = 0.19).
- BACE1 levels were ∼200% of wild-type in 15–18-month-old 5XFAD mice; BACE1+/− reduced BACE1 by ∼50% but residual BACE1 remained equivalent to wild-type. Phospho-eIF2α was ∼9-fold elevated in old 5XFAD and remained ∼6-fold elevated in BACE1+/−·5XFAD; Sal 003-induced phospho-eIF2α elevation increased BACE1 in 6-month-old 5XFAD slices.
Methods
- Crossbred heterozygous BACE1 knockout mice with 5XFAD transgenic mice to generate wild-type, BACE1+/−, 5XFAD, and BACE1+/−·5XFAD genotypes; tested at 6 months and 15–18 months of age.
- Behavioral testing used the spontaneous alternation Y-maze; biochemical measures included immunoblot for BACE1, APP, C99, phospho-eIF2α, ChAT, and β-actin; ChAT immunohistochemistry in medial septum/vertical limb of diagonal band; and Aβ42 sandwich ELISA.
- Brain slices from 6-month-old 5XFAD mice were treated with Sal 003 (30 µM) to inhibit phospho-eIF2α phosphatase; statistical analysis used one-way ANOVA with post-hoc Fisher’s PLSD, p < 0.05.
Limitations
- The paper does not state a dedicated limitations section.
- Evident from the text: findings are restricted to the 5XFAD mouse model and two age points (6 months and 15–18 months), with small group sizes (n = 4–12 per group in reported experiments).
- Evident from the text: BACE1 reduction was achieved by heterozygous genetic deletion, not pharmacological BACE1 inhibition, so direct clinical dosing implications remain untested.
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40 Own result · 22 Own interpretation · 20 Not checked yet · 1 Own method · 1 No basis given
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“ChAT levels in the hippocampus of both 5XFAD and BACE1+/−·5XFAD mice at 15–18 months of age were significantly lower than those of wild-type control mice (F (2,24) = 10.51, p<0.05)”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Results > Abilities of partial BACE1 reduction to rescue cholinergic neurodegeneration decline with age in 5XFAD mice
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In the paper
“Aβ42 levels were not significantly different between BACE1+/−·5XFAD and 5XFAD mice at 15–18 months of age (F (1,6) = 2.23, p = 0.19).”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Results > Age-related effects of partial BACE1 reduction on APP processing and Aβ levels in 5XFAD mice
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In the paper
“BACE1+/− ablation significantly lowered excessive levels of Aβ42 in 6-month-old 5XFAD mouse brains (F (1,6) = 23.53, p<0.05).”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Results > Age-related effects of partial BACE1 reduction on APP processing and Aβ levels in 5XFAD mice
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In the paper
“Levels of the β-secretase-cleaved C-terminal fragment (C99) were significantly reduced in BACE1+/−·5XFAD mice at 6 months of age as compared to 5XFAD mice (F (1,10) = 7.37, p<0.05)”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Results > Age-related effects of partial BACE1 reduction on APP processing and Aβ levels in 5XFAD mice
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In the paper
“Post-hoc Fisher's PLSD test indicated only a trend toward slight increases in ChAT levels of BACE1+/−·5XFAD mice compared to those of 5XFAD littermates (p = 0.10).”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Results > Abilities of partial BACE1 reduction to rescue cholinergic neurodegeneration decline with age in 5XFAD mice
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In the paper
“while it was no longer able to significantly influence levels of these β-products in 15–18-month-old 5XFAD mouse brains (∼18% and ∼20% reductions, respectively).”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Results > Age-related effects of partial BACE1 reduction on APP processing and Aβ levels in 5XFAD mice
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In the paper
“the spatial working memory deficits were rescued to wild-type levels in 5XFAD mice with BACE1+/− genotype, which exhibited significantly higher spontaneous alternation than did 5XFAD mice (p<0.05)”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Results > Abilities of partial BACE1 reduction to rescue memory dysfunction decline with age in 5XFAD mice
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“the residual levels of BACE1 in older BACE1+/−·5XFAD mouse brains were equivalent to those of wild-type controls.”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Results > Age-related effects of partial BACE1 reduction on BACE1 and phospho-eIF2α levels in 5XFAD mice
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In the paper
“the elevated levels of C99 were no longer significantly affected by BACE1+/− deletion at this advanced age (F (1,9) = 2.57, p = 0.14).”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Results > Age-related effects of partial BACE1 reduction on APP processing and Aβ levels in 5XFAD mice
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“C99 levels in 15–18-month-old 5XFAD mouse brains were significantly higher than those of 6-month-old 5XFAD brains (∼172%) (F (1,10) = 10.71, p<0.05)”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Results > Age-related effects of partial BACE1 reduction on APP processing and Aβ levels in 5XFAD mice
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In the paper
“ChAT levels were significantly reduced in 5XFAD mice at 6 months of age compared with wild-type controls”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Results > Abilities of partial BACE1 reduction to rescue cholinergic neurodegeneration decline with age in 5XFAD mice
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In the paper
“Heterozygous gene knockout also reduced cerebral BACE1 expression by ∼50% in 5XFAD mice at this advanced age (p<0.05).”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Results > Age-related effects of partial BACE1 reduction on BACE1 and phospho-eIF2α levels in 5XFAD mice
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In the paper
“ChAT was restored to wild-type levels in 5XFAD mice with BACE1+/− genotype (F (2,18) = 8.89, p<0.05)”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Results > Abilities of partial BACE1 reduction to rescue cholinergic neurodegeneration decline with age in 5XFAD mice
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In the paper
“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”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Results > Abilities of partial BACE1 reduction to rescue cholinergic neurodegeneration decline with age in 5XFAD mice
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In the paper
“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)”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Results > Age-related effects of partial BACE1 reduction on BACE1 and phospho-eIF2α levels in 5XFAD mice
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In the paper
“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)”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Results > Abilities of partial BACE1 reduction to rescue memory dysfunction decline with age in 5XFAD mice
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In the paper
“5XFAD mice showed significantly reduced levels of spontaneous alternation performance in the Y-maze compared with wild-type controls (p<0.05)”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Results > Abilities of partial BACE1 reduction to rescue memory dysfunction decline with age in 5XFAD mice
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In the paper
“BACE1 levels were not different between 5XFAD and wild-type mice at 6 months of age”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Results > Age-related effects of partial BACE1 reduction on BACE1 and phospho-eIF2α levels in 5XFAD mice
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“the percent alternation was indistinguishable between BACE1+/− and wild-type mice at 6 or 15–18 months of age”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Results > Abilities of partial BACE1 reduction to rescue memory dysfunction decline with age in 5XFAD mice
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“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).”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Results > Age-related effects of partial BACE1 reduction on APP processing and Aβ levels in 5XFAD mice
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In the paper
“BACE1 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)”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Results > Age-related effects of partial BACE1 reduction on BACE1 and phospho-eIF2α levels in 5XFAD mice
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In the paper
“the full-length APP expression levels were not affected by BACE1+/− mutation in 5XFAD mice at 6 months or 15–18 months of age”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Results > Age-related effects of partial BACE1 reduction on APP processing and Aβ levels in 5XFAD mice
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In the paper
“BACE1+/− 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)”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Results > Age-related effects of partial BACE1 reduction on BACE1 and phospho-eIF2α levels in 5XFAD mice
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“they remained strikingly elevated compared with wild-type controls (∼6-fold) consistent with the persistent BACE1 upregulation.”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Results > Age-related effects of partial BACE1 reduction on BACE1 and phospho-eIF2α levels in 5XFAD mice
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“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.”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Results > Abilities of partial BACE1 reduction to rescue cholinergic neurodegeneration decline with age in 5XFAD mice
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“while ChAT-positive neuron number was completely restored to wild-type levels in BACE1+/−·5XFAD mice (F (2,13) = 9.80, p<0.05)”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Results > Abilities of partial BACE1 reduction to rescue cholinergic neurodegeneration decline with age in 5XFAD mice
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In the paper
“Although phospho-eIF2α levels in BACE1+/−·5XFAD mice were lower than those of 5XFAD mice at this advanced age (p<0.05)”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Results > Age-related effects of partial BACE1 reduction on BACE1 and phospho-eIF2α levels in 5XFAD mice
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“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.”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Results > Abilities of partial BACE1 reduction to rescue memory dysfunction decline with age in 5XFAD mice
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In the paper
“Sal 003-induced increases in phospho-eIF2α elevated BACE1 levels”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Results > Age-related effects of partial BACE1 reduction on BACE1 and phospho-eIF2α levels in 5XFAD mice
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“upregulation was attenuated to a certain degree but was largely maintained (∼6-fold) in BACE1+/−·5XFAD mice at this advanced age.”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Discussion
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In the paper
“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%).”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Discussion
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In the paper
“It should also be noted that levels of the full-length APP were not altered in BACE1+/−·5XFAD mice”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Discussion
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In the paper
“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.”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Discussion
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In the paper
“5XFAD model mice exhibited hippocampal cholinergic deficits associated with significant neuron loss in the medial septum and the vertical limb of the diagonal band.”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Discussion
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In the paper
“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.”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Discussion
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In the paper
“phospho-eIF2α is demonstrated to be a critical mediator of the post-transcriptional BACE1 upregulation in sporadic AD and 5XFAD mouse brains [33].”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Discussion
What the sources say
- Not checked yetcites [33] O'Connor T Sadleir KR Maus E Velliquette RA Zhao J 2008 Phosphorylation of the translation initiation factor eIF2α increases BACE1 levels and promotes amyloidogenesis. Neuron 60 988 1009 19109907 PMC2667382
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In the paper
“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.”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Discussion
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In the paper
“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.”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Results > Age-related effects of partial BACE1 reduction on BACE1 and phospho-eIF2α levels in 5XFAD mice
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In the paper
“elevations in BACE1 levels (∼2-fold) have been demonstrated to occur in brains of 5XFAD mice as amyloid pathology progresses [9], [21], [26].”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Introduction
What the sources say
- Not checked yetcites [9] Ohno M Cole SL Yasvoina M Zhao J Citron M 2007 BACE1 gene deletion prevents neuron loss and memory deficits in 5XFAD APP/PS1 transgenic mice. Neurobiol Dis 26 134 145 17258906 PMC1876698
- Not checked yetcites [21] Devi L Ohno M 2010 Genetic reductions of β-site amyloid precursor protein-cleaving enzyme 1 and amyloid-β ameliorate impairment of conditioned taste aversion memory in 5XFAD Alzheimer's disease model mice. Eur J Neurosci 31 110 118 20092558 PMC2887274
- Not checked yetcites [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
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In the paper
“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.”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Discussion
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In the paper
“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.”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Discussion
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In the paper
“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.”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Introduction
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In the paper
“demonstrating that BACE1 is a direct translational target of the activated phospho-eIF2α pathway in the 5XFAD mouse model of AD.”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Results > Age-related effects of partial BACE1 reduction on BACE1 and phospho-eIF2α levels in 5XFAD mice
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In the paper
“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.”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Discussion
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In the paper
“These results indicate a dissociation between C99 and BACE1 levels in the older BACE1+/−·5XFAD mouse brains.”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Discussion
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In the paper
“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.”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Discussion
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In the paper
“suggesting that merely overexpressing multiple FAD mutant forms of APP is unlikely to cause cholinergic or cognitive defects in 5XFAD mice.”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Discussion
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In the paper
“The results not only provide the first demonstration that partial suppression of BACE1 is effective in preventing cholinergic neurodegeneration associated with AD”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Discussion
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In the paper
“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.”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
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- Rests on an assumption: C99 is a direct β-cleavage metabolite of APP.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Discussion
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In the paper
“This mechanism is likely to contribute to dampening and eventually abolishing the beneficial effects of BACE1+/− deletion against memory deficits.”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Discussion
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In the paper
“Taken together, these results indicate that the rise in phospho-eIF2α underlies the age-dependent increase in BACE1 in 5XFAD mice”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Discussion
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In the paper
“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].”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Discussion
What the sources say
- Not checked yetcites [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 yetcites [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 yetcites [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
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In the paper
“central lowering of Aβ levels following systemic administration of future BACE1 inhibitor drugs may be limited [16], [17]”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Introduction
What the sources say
- Not checked yetcites [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 yetcites [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
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In the paper
“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.”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Discussion
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In the paper
“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.”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
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- It may state two separate claims as one. 18
- Probably not a substantial claim. 12
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“At 6 months of age, the 5XFAD-associated increase in phospho-eIF2α level was marginal and it was completely abolished in BACE1+/−·5XFAD mice (F (2,11) = 25.76, p<0.05)”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Results > Age-related effects of partial BACE1 reduction on BACE1 and phospho-eIF2α levels in 5XFAD mice
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Post-hoc Fisher's PLSD test revealed no significant difference in alternation performances between 5XFAD and BACE1+/−·5XFAD mice (p = 0.24), indicating that BACE1+/− deletion failed to improve the spatial working memory defect in 5XFAD mice at this advanced age.”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Results > Abilities of partial BACE1 reduction to rescue memory dysfunction decline with age in 5XFAD mice
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In the paper
“the number of ChAT-immunoreactive neurons in 5XFAD and BACE1+/−·5XFAD mice at 15–18 months of age was significantly lower than that of wild-type control mice (F (2,13) = 8.49, p<0.05) and was indistinguishable from each other according to post-hoc Fisher's PLSD test (p = 0.32).”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Results > Abilities of partial BACE1 reduction to rescue cholinergic neurodegeneration decline with age in 5XFAD mice
plain- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“BACE1+/− deletion significantly suppressed the β-cleavage of APP in 5XFAD mice at 6 months of age resulting in reduced levels of C99 and Aβ42 (by ∼53% and ∼67%, respectively)”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Results > Age-related effects of partial BACE1 reduction on APP processing and Aβ levels in 5XFAD mice
plaindirect- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Importantly, we found that BACE1+/− deletion restored the cholinergic defects to normal consistent with improvements in hippocampal spatial memory function in 5XFAD mice at 6 months of age.”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Although heterozygous knockout also reduced BACE1 expression by ∼50% in 15–18-month-old 5XFAD mice in concordance with the reduction in gene copy number, their C99 levels were not significantly lower than age-matched 5XFAD levels.”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Discussion
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“5XFAD mice begin to develop visible amyloid deposition as early as 2 months of age and exhibit memory declines on hippocampus-dependent tasks between 4–6 months with moderate Aβ accumulation [8], [28], [29], [30], [31].”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Introduction
What the sources say
- Not checked yetcites [8] Ohno M Chang L Tseng W Oakley H Citron M 2006 Temporal memory deficits in Alzheimer's mouse models: rescue by genetic deletion of BACE1. Eur J Neurosci 23 251 260 16420434
- Not checked yetcites [28] Oakley H Cole SL Logan S Maus E Shao P 2006 Intraneuronal β-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer's disease mutations: potential factors in amyloid plaque formation. J Neurosci 26 10129 10140 17021169 PMC6674618
- Not checked yetcites [29] Kimura R Ohno M 2009 Impairments in remote memory stabilization precede hippocampal synaptic and cognitive failures in 5XFAD Alzheimer mouse model. Neurobiol Dis 33 229 235 19026746 PMC2741400
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“the β-secretase (BACE1: β-site amyloid precursor protein cleaving enzyme 1), which is responsible for initiating the production of Aβ, represents an excellent therapeutic target for the treatment of AD [3], [4], [5], [6].”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Introduction
What the sources say
- Not checked yetcites [3] Citron M 2004 β-Secretase inhibition for the treatment of Alzheimer's disease–promise and challenge. Trends Pharmacol Sci 25 92 97 15102495
- Not checked yetcites [4] Ohno M 2006 Genetic and pharmacological basis for therapeutic inhibition of β- and γ-secretases in mouse models of Alzheimer's memory deficits. Rev Neurosci 17 429 454 17139843
- Not checked yetcites [5] Ohno M 2008 β-Secretase as a prime therapeutic target for Alzheimer's disease: a perspective from mouse model studies. Araki W Recent Advances in the Biology of Secretases, Key Proteases in Alzheimer's Disease Kerala Research Signpost 1 25
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. It may be too vague to check against evidence.
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In the paper
“partial reduction of BACE1 suffices to attenuate Aβ-related pathology and rescue synaptic and memory deficits in mouse models of AD [18], [19], [20], [21], [22].”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Introduction
What the sources say
- Not checked yetcites [18] Singer O Marr RA Rockenstein E Crews L Coufal NG 2005 Targeting BACE1 with siRNAs ameliorates Alzheimer disease neuropathology in a transgenic model. Nat Neurosci 8 1343 1349 16136043
- Not checked yetcites [19] Chang WP Downs D Huang XP Da H Fung KM 2007 Amyloid-β reduction by memapsin 2 (β-secretase) immunization. FASEB J 21 3184 3196 17494994
- Not checked yetcites [20] McConlogue L Buttini M Anderson JP Brigham EF Chen KS 2007 Partial reduction of BACE1 has dramatic effects on Alzheimer plaque and synaptic pathology in APP transgenic mice. J Biol Chem 282 26326 26334 17616527
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“evidence is accumulating that BACE1 expression and activity levels are significantly elevated in sporadic AD brains, which is considered a crucial contributing factor in the pathogenesis of this enigmatic disease [23], [24], [25], [26], [27].”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Introduction
What the sources say
- Not checked yetcites [23] Fukumoto H Cheung BS Hyman BT Irizarry MC 2002 β-Secretase protein and activity are increased in the neocortex in Alzheimer disease. Arch Neurol 59 1381 1389 12223024
- Not checked yetcites [24] Li R Lindholm K Yang LB Yue X Citron M 2004 Amyloid β peptide load is correlated with increased β-secretase activity in sporadic Alzheimer's disease patients. Proc Natl Acad Sci USA 101 3632 3637 14978286 PMC373514
- Not checked yetcites [25] Yang LB Lindholm K Yan R Citron M Xia W 2003 Elevated β-secretase expression and enzymatic activity detected in sporadic Alzheimer disease. Nat Med 9 3 4 12514700
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“previous studies also showed that the effects of BACE1+/− deletion in reducing total Aβ levels and plaque load in PDAPP transgenic mice become smaller during the course of disease progression [20]”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Discussion
What the sources say
- Not checked yetcites [20] McConlogue L Buttini M Anderson JP Brigham EF Chen KS 2007 Partial reduction of BACE1 has dramatic effects on Alzheimer plaque and synaptic pathology in APP transgenic mice. J Biol Chem 282 26326 26334 17616527
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
In the paper
“complete deletion of BACE1 (BACE1−/−), which abrogates Aβ production, can still rescue impaired spontaneous alternation performance concomitant with the prevention of Aβ deposition and neuronal loss in 5XFAD mice at this advanced age [9].”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Discussion
What the sources say
- Not checked yetcites [9] Ohno M Cole SL Yasvoina M Zhao J Citron M 2007 BACE1 gene deletion prevents neuron loss and memory deficits in 5XFAD APP/PS1 transgenic mice. Neurobiol Dis 26 134 145 17258906 PMC1876698
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“spontaneous alternation in the Y-maze that represents a measure of spatial working memory [34]”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Results > Abilities of partial BACE1 reduction to rescue memory dysfunction decline with age in 5XFAD mice
What the sources say
- Not checked yetcites [34] Lalonde R 2002 The neurobiological basis of spontaneous alternation. Neurosci Biobehav Rev 26 91 104 11835987
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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Probably not a substantial claim.
None of the sources cited for this claim have been checked yet.
In the paper
“recent studies suggest that phosphorylation of the eukaryotic translation initiation factor-2α (eIF2α) plays an important role in mediating the post-transcriptional upregulation of BACE1 in human AD and 5XFAD mouse brains [32], [33].”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Introduction
What the sources say
- Not checked yetcites [32] Chang RC Wong AK Ng HK Hugon J 2002 Phosphorylation of eukaryotic initiation factor-2α (eIF2α) is associated with neuronal degeneration in Alzheimer's disease. Neuroreport 13 2429 2432 12499843
- Not checked yetcites [33] O'Connor T Sadleir KR Maus E Velliquette RA Zhao J 2008 Phosphorylation of the translation initiation factor eIF2α increases BACE1 levels and promotes amyloidogenesis. Neuron 60 988 1009 19109907 PMC2667382
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Together, our results indicate that partial reduction of BACE1 is not sufficient to block the phospho-eIF2α-dependent BACE1 elevation during the progression of AD, thus limiting its abilities to reduce cerebral Aβ/C99 levels and rescue memory deficits and cholinergic neurodegeneration.”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Abstract
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: Approximately 50% BACE1 suppression is likely efficacious.
None of the sources cited for this claim have been checked yet.
In the paper
“genetic deletion of BACE1 prevents AD-like pathologies and improves cognitive impairments in different transgenic mouse models [7], [8], [9], [10].”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Introduction
What the sources say
- Not checked yetcites [7] Ohno M Sametsky EA Younkin LH Oakley H Younkin SG 2004 BACE1 deficiency rescues memory deficits and cholinergic dysfunction in a mouse model of Alzheimer's disease. Neuron 41 27 33 14715132
- Not checked yetcites [8] Ohno M Chang L Tseng W Oakley H Citron M 2006 Temporal memory deficits in Alzheimer's mouse models: rescue by genetic deletion of BACE1. Eur J Neurosci 23 251 260 16420434
- Not checked yetcites [9] Ohno M Cole SL Yasvoina M Zhao J Citron M 2007 BACE1 gene deletion prevents neuron loss and memory deficits in 5XFAD APP/PS1 transgenic mice. Neurobiol Dis 26 134 145 17258906 PMC1876698
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“the β-secretase (BACE1: β-site amyloid precursor protein cleaving enzyme 1), which is responsible for initiating the production of Aβ, represents an excellent therapeutic target for the treatment of AD [3], [4], [5], [6].”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Introduction
What the sources say
- Not checked yetcites [3] Citron M 2004 β-Secretase inhibition for the treatment of Alzheimer's disease–promise and challenge. Trends Pharmacol Sci 25 92 97 15102495
- Not checked yetcites [4] Ohno M 2006 Genetic and pharmacological basis for therapeutic inhibition of β- and γ-secretases in mouse models of Alzheimer's memory deficits. Rev Neurosci 17 429 454 17139843
- Not checked yetcites [5] Ohno M 2008 β-Secretase as a prime therapeutic target for Alzheimer's disease: a perspective from mouse model studies. Araki W Recent Advances in the Biology of Secretases, Key Proteases in Alzheimer's Disease Kerala Research Signpost 1 25
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
None of the sources cited for this claim have been checked yet.
In the paper
“The septohippocampal cholinergic pathway has an established role in mediating spatial working memory including spontaneous alternation performance in the Y-maze [35], [36], [37].”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Results > Abilities of partial BACE1 reduction to rescue cholinergic neurodegeneration decline with age in 5XFAD mice
What the sources say
- Not checked yetcites [35] Ohno M Yamamoto T Watanabe S 1992 Effects of intrahippocampal injections of N-methyl-D-aspartate receptor antagonists and scopolamine on working and reference memory assessed in rats by a three-panel runway task. J Pharmacol Exp Ther 263 943 950 1361577
- Not checked yetcites [36] Feasey-Truger KJ Li BH ten Bruggencate G 1992 Lesions of the medial septum which produce deficits in working/spatial memory do not impair long-term potentiation in the CA3 region of the rat hippocampus in vivo. Brain Res 591 296 304 1446243
- Not checked yetcites [37] Chang Q Gold PE 2004 Impaired and spared cholinergic functions in the hippocampus after lesions of the medial septum/vertical limb of the diagonal band with 192 IgG-saporin. Hippocampus 14 170 179 15098723
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
None of the sources cited for this claim have been checked yet.
In the paper
“At ≥9 months of age, 5XFAD mice show severe memory deficits together with further developed Aβ pathology and marked synaptic degeneration and neuronal loss [9], [21], [28], [30], [31].”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Introduction
What the sources say
- Not checked yetcites [9] Ohno M Cole SL Yasvoina M Zhao J Citron M 2007 BACE1 gene deletion prevents neuron loss and memory deficits in 5XFAD APP/PS1 transgenic mice. Neurobiol Dis 26 134 145 17258906 PMC1876698
- Not checked yetcites [21] Devi L Ohno M 2010 Genetic reductions of β-site amyloid precursor protein-cleaving enzyme 1 and amyloid-β ameliorate impairment of conditioned taste aversion memory in 5XFAD Alzheimer's disease model mice. Eur J Neurosci 31 110 118 20092558 PMC2887274
- Not checked yetcites [28] Oakley H Cole SL Logan S Maus E Shao P 2006 Intraneuronal β-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer's disease mutations: potential factors in amyloid plaque formation. J Neurosci 26 10129 10140 17021169 PMC6674618
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“However, these phenotypes are not observed in BACE1+/− knockout mice, suggesting that potential mechanism-based side effects might occur only in completely abolishing BACE1 activity but not in partially inhibiting it.”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: These phenotypes (liabilities of complete BACE1 deletion) are not observed in BACE1+/− knockout mice.
None of the sources cited for this claim have been checked yet.
In the paper
“In line with the discovery of various BACE1 physiological substrates besides APP such as neuregulins and β-subunits of the voltage-gated sodium channel, recent studies reveal some liabilities of complete BACE1 deletion including hypomyelination and altered synaptic functions or neuronal activities [4], [5], [6].”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Discussion
What the sources say
- Not checked yetcites [4] Ohno M 2006 Genetic and pharmacological basis for therapeutic inhibition of β- and γ-secretases in mouse models of Alzheimer's memory deficits. Rev Neurosci 17 429 454 17139843
- Not checked yetcites [5] Ohno M 2008 β-Secretase as a prime therapeutic target for Alzheimer's disease: a perspective from mouse model studies. Araki W Recent Advances in the Biology of Secretases, Key Proteases in Alzheimer's Disease Kerala Research Signpost 1 25
- Not checked yetcites [6] Cole SL Vassar R 2007 The Alzheimer's disease β-secretase enzyme, BACE1. Mol Neurodegener 2 22 18005427 PMC2211305
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“accumulation of the amyloid-β (Aβ) peptide plays a central role in triggering a pathogenic cascade ultimately leading to neuronal death and profound memory deficits [1], [2].”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Introduction
What the sources say
- Not checked yetcites [1] Hardy JA Higgins GA 1992 Alzheimer's disease: the amyloid cascade hypothesis. Science 256 184 185 1566067
- Not checked yetcites [2] Hardy J Selkoe DJ 2002 The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 297 353 356 12130773
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“but also indicate that neurotoxic Aβ42 and/or C99 species are responsible for killing cholinergic neurons.”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Discussion
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Notably, phosphorylation of eIF2α, which increases age-dependently and induces BACE1 elevation in the 5XFAD model, seems to be important for determining the abilities of partial BACE1 reduction to improve cholinergic and mnemonic deficits.”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Interestingly, transgenic overexpression or central administration of the potentially amyloidogenic C99 fragments has been reported to induce memory defects and neurodegeneration [45], [46], [47], [48], [49].”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Discussion
What the sources say
- Not checked yetcites [45] Lee KW Im JY Song JS Lee SH Lee HJ 2006 Progressive neuronal loss and behavioral impairments of transgenic C57BL/6 inbred mice expressing the carboxy terminus of amyloid precursor protein. Neurobiol Dis 22 10 24 16289866
- Not checked yetcites [46] Nalbantoglu J Tirado-Santiago G Lahsaini A Poirier J Goncalves O 1997 Impaired learning and LTP in mice expressing the carboxy terminus of the Alzheimer amyloid precursor protein. Nature 387 500 505 9168112
- Not checked yetcites [47] Berger-Sweeney J McPhie DL Arters JA Greenan J Oster-Granite ML 1999 Impairments in learning and memory accompanied by neurodegeneration in mice transgenic for the carboxyl-terminus of the amyloid precursor protein. Brain Res Mol Brain Res 66 150 162 10095087
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“All experiments were done blind with respect to the genotype of the mice at 6 and 15–18 months of age, and were conducted with the approval of the Nathan Kline Institute Animal Care and Use Committee (AP2008-268).”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Materials and Methods > Animals
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“Consistent with the so-called “cholinergic hypothesis” of AD [50], several APP transgenic mouse models reproduce cholinergic neurodegeneration as evidenced by dystrophic neurites, decreased fiber density in the hippocampus and cortex, and reductions in the medial septum and basal forebrain neuron volume/number [51], [52], [53], [54];”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Discussion
What the sources say
- Not checked yetcites [51] Bellucci A Luccarini I Scali C Prosperi C Giovannini MG 2006 Cholinergic dysfunction, neuronal damage and axonal loss in TgCRND8 mice. Neurobiol Dis 23 260 272 16766197
- Not checked yetcites [52] Christensen DZ Bayer TA Wirths O 2010 Intracellular Aβ triggers neuron loss in the cholinergic system of the APP/PS1KI mouse model of Alzheimer's disease. Neurobiol Aging 31 1153 1163 18771817
- Not checked yetcites [53] Boncristiano S Calhoun ME Kelly PH Pfeifer M Bondolfi L 2002 Cholinergic changes in the APP23 transgenic mouse model of cerebral amyloidosis. J Neurosci 22 3234 3243 11943824 PMC6757538
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The failure of BACE1+/− ablation to rescue the septohippocampal degeneration found in 15–18-month-old 5XFAD mice in parallel with no amelioration of memory function supports the view that Aβ/C99-dependent cholinergic dysfunction represents a critical mechanism responsible for memory impairments in 5XFAD mice.”
§ Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper relies on this without support.
Approximately 50% BACE1 suppression is likely efficacious.
“Given ∼50% BACE1 suppression generally accepted as it is likely efficacious, we used BACE1+/− mice as a model system to evaluate the efficacies of partial and therapeutic inhibition of BACE1.”
The paper relies on this without support.
C99 is a direct β-cleavage metabolite of APP.
“Since C99 is a direct β-cleavage metabolite of APP, the high residual levels of C99 may reflect some accumulating species of C99 (similar to Aβ peptides) that could be less sensitive to reduction by BACE1+/− deletion in 15–18-month-old 5XFAD mice.”
The paper relies on this without support.
These phenotypes (liabilities of complete BACE1 deletion) are not observed in BACE1+/− knockout mice.
“However, these phenotypes are not observed in BACE1+/− knockout mice, suggesting that potential mechanism-based side effects might occur only in completely abolishing BACE1 activity but not in partially inhibiting it.”
The paper relies on this without support.
The mechanisms for cholinergic neuron loss in AD are largely unknown.
“however, the mechanisms for cholinergic neuron loss is yet largely unknown.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“Significant memory impairment is observed before six months of age [35,37,38]”
From Centella Asiatica Improves Memory and Promotes Antioxidative Signaling in 5XFAD Mice (2019) · cites this paper as [37]
Statistics recomputed
Every reported test result, recomputed from its test statistic and degrees of freedom. A result shows as not adding up only once an independent check has confirmed it.
- ConsistentF(3, 32) = 4.78reported p < .05 · recomputed p = .007
“F (3,32) = 4.78, p < .05”
- ConsistentF(3, 33) = 11.38reported p < .05 · recomputed p < .001
“F (3,33) = 11.38, p < .05”
- ConsistentF(2, 18) = 8.89reported p < .05 · recomputed p = .002
“F (2,18) = 8.89, p < .05”
- ConsistentF(2, 24) = 10.51reported p < .05 · recomputed p < .001
“F (2,24) = 10.51, p < .05”
- ConsistentF(2, 13) = 9.8reported p < .05 · recomputed p = .003
“F (2,13) = 9.80, p < .05”
- ConsistentF(2, 13) = 8.49reported p < .05 · recomputed p = .004
“F (2,13) = 8.49, p < .05”
- ConsistentF(1, 10) = 7.37reported p < .05 · recomputed p = .022
“F (1,10) = 7.37, p < .05”
- ConsistentF(1, 10) = 10.71reported p < .05 · recomputed p = .008
“F (1,10) = 10.71, p < .05”
- ConsistentF(1, 9) = 2.57reported p = .14 · recomputed p = .143
“F (1,9) = 2.57, p = .14”
- ConsistentF(1, 6) = 48.41reported p < .05 · recomputed p < .001
“F (1,6) = 48.41, p < .05”
- ConsistentF(1, 6) = 23.53reported p < .05 · recomputed p = .003
“F (1,6) = 23.53, p < .05”
- ConsistentF(1, 6) = 2.23reported p = .19 · recomputed p = .186
“F (1,6) = 2.23, p = .19”
- ConsistentF(2, 18) = 11.25reported p < .05 · recomputed p < .001
“F (2,18) = 11.25, p < .05”
- ConsistentF(2, 11) = 31.91reported p < .05 · recomputed p < .001
“F (2,11) = 31.91, p < .05”
- ConsistentF(2, 11) = 25.76reported p < .05 · recomputed p < .001
“F (2,11) = 25.76, p < .05”
- ConsistentF(2, 21) = 11.72reported p < .05 · recomputed p < .001
“F (2,21) = 11.72, p < .05”
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Self-check results appear here once an independent check has confirmed them.
Citations
Cites
The mouse brain in stereotaxic coordinates
Konsman, J. (2003) · Psychoneuroendocrinology · doi:10.1016/s0306-4530(03)00088-x · Cited by 16,796 · cited 1×
“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
Hardy, J., & Selkoe, D. J. (2002) · Science · doi:10.1126/science.1072994 · Cited by 13,864
The Mouse Brain in Stereotaxic Coordinates
Paxinos, G. (2001) · Cited by 12,859
Alzheimer's disease: the amyloid cascade hypothesis
Hardy, J. A., & Higgins, G. A. (1992) · Science · doi:10.1126/science.1566067 · Cited by 7,484 · cited 1×
“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
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BACE1 is the major β-secretase for generation of Aβ peptides by neurons
Cai, H., Wang, Y., McCarthy, D. B., Wen, H., Borchelt, D., Price, D. L., & Wong, P. C. (2001) · Nature Neuroscience · doi:10.1038/85064 · Cited by 1,087
The neurobiological basis of spontaneous alternation
Lalonde, R. (2002) · Neuroscience & Biobehavioral Reviews · doi:10.1016/s0149-7634(01)00041-0 · Cited by 857 · cited 1×
“represents a measure of spatial working memory [34] (Fig.”
BackgroundThe secretases: enzymes with therapeutic potential in Alzheimer disease
De Strooper, B., Vassar, R., & Golde, T. (2010) · Nature Reviews Neurology · doi:10.1038/nrneurol.2009.218 · Cited by 799
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
Cited by
Sorted by citations
Microglia in Neuroinflammation and Neurodegeneration: From Understanding to Therapy
Muzio, L., Viotti, A., & Martino, G. (2021) · Frontiers in Neuroscience · doi:10.3389/fnins.2021.742065 · Cited by 581
Devi, L., & Ohno, M. (2012) · Neuropsychopharmacology · doi:10.1038/npp.2011.191 · Cited by 282
“…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 253
Kocahan, S., & Doğan, Z. (2017) · Clinical Psychopharmacology and Neuroscience · doi:10.9758/cpn.2017.15.1.1 · Cited by 246
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
“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].”
BackgroundResultInfluential
Metadata
- Authors
- Devi, L., & Ohno, M.
- Affiliations
- New York University (US)
- Corresponding author
- Ohno, Masuo
- ORCID
- Ohno, Masuo
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2010-09-23
- Volume
- 5
- Issue
- 9
- Pages
- e12974
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC2944882
- OpenAlex
- W2012590437
- Cited by
- 140
- References
- 61
- Citations by year
- 2026: 8 · 2025: 8 · 2024: 14 · 2023: 9 · 2022: 16 · 2021: 11 · 2020: 8 · 2019: 8 · 2018: 5 · 2017: 9 · 2016: 6 · 2015: 12 · 2014: 10 · 2013: 6 · 2012: 4
- FWCI
- 3.25
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Alzheimer's Association (IIRG-08-91231)
- National Institutes of Health
- National Institute of Mental Health (R01MH067251)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Pharmacology (medical) › Cholinesterase and Neurodegenerative Diseases
- Keywords
- eIF2α phosphorylation, Alzheimer's disease, 5xFAD mice, amyloid-beta, cholinergic neurodegeneration, memory impairment, C99, amyloid-beta 42, translation initiation, gene dosage, BACE1 inhibition
- MeSH terms
- Alzheimer Disease, Animals, Cholinergic Fibers, Disease Models, Animal, Female, Humans, Male, Memory, Mice, Inbred C57BL, Mice, Transgenic, Nerve Degeneration, Phosphorylation, Eukaryotic Initiation Factor-2, Aspartic Acid Endopeptidases, Mice, Knockout, Mice, Amyloid Precursor Protein Secretases
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