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• W2012590437 endingPage "e12974" @default.
• W2012590437 startingPage "e12974" @default.
• W2012590437 abstract "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." @default.
• W2012590437 created "2016-06-24" @default.
• W2012590437 creator A5033371779 @default.
• W2012590437 creator A5059299823 @default.
• W2012590437 date "2010-09-23" @default.
• W2012590437 modified "2023-10-18" @default.
• W2012590437 title "Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice" @default.
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• W2012590437 doi "https://doi.org/10.1371/journal.pone.0012974" @default.
• W2012590437 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/2944882" @default.
• W2012590437 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/20886088" @default.
• W2012590437 hasPublicationYear "2010" @default.
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