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

beta-Site APP-cleaving enzyme 1 (BACE1) initiates amyloid-beta (A beta) 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 (similar to 100%) and elevated (similar to 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 A beta 42 and the beta-secretase-cleaved C-terminal fragment (C99) in 6-month-old 5XFAD mouse brains, while these neurotoxic beta-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 similar to 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 eIF2 alpha, an important mediator of BACE1 elevation, was dramatically increased (similar to 9-fold) in 15-18-month-old 5XFAD mice and remained highly upregulated (similar to 6-fold) in age-matched BACE1(+/-) . 5XFAD mice. Together, our results indicate that partial reduction of BACE1 is not sufficient to block the phospho-eIF2 alpha-dependent BACE1 elevation during the progression of AD, thus limiting its abilities to reduce cerebral A beta/C99 levels and rescue memory deficits and cholinergic neurodegeneration.