Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice

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.