Mechanisms that lessen benefits of β-secretase reduction in a mouse model of Alzheimer's disease

The beta-secretase enzyme BACE1 (beta-site amyloid precursor protein-cleaving enzyme 1), which initiates amyloid-beta (A beta) production, is an excellent therapeutic target for Alzheimer's disease (AD). However, recent evidence raises concern that BACE1-inhibiting approaches may encounter dramatic declines in their abilities to ameliorate AD-like pathology and memory deficits during disease progression. Here, we used BACE1 haploinsufficiency as a therapeutic relevant model to evaluate the efficacy of partial inhibition of this enzyme. Specifically, we crossed BACE1 (+/-) mice with 5XFAD transgenic mice and investigated the mechanisms by which A beta accumulation and related memory impairments become less sensitive to rescue by BACE1 (+/-) reduction. Haploinsufficiency lowered BACE1 expression by similar to 50% in 5XFAD mice regardless of age in concordance with reduction in gene copy number. However, profound A beta plaque pathology and memory deficits concomitant with BACE1 equivalent to wild-type control levels remained in BACE1 (+/-).5XFAD mice with advanced age (15-18 months old). Therefore, BACE1 haploinsufficiency is not sufficient to block the elevation of BACE1 expression (approximately twofold), which is also reported to occur during human A beta progression, in 5XFAD mice. Our investigation revealed that PERK (PKR-endoplasmic reticulurn-related kinase)-dependent activation of eIF2 alpha (eukaryotic translation initiation factor-2 alpha) accounts for the persistent BACE1 upregulation in BACE1 (+/-). 5XFAD mouse brains at 15-18 months of age. Moreover, BACE1 haploinsufficiency was also no longer able to prevent reduction in the expression of neprilysin, a crucial A beta-degrading enzyme, in 5XFAD mice with advanced age. These findings demonstrate that partial BACE1 suppression cannot attenuate deleterious BACE1-elevating or neprilysin-reducing mechanisms, limiting its capabilities to reduce cerebral A beta accumulation and rescue memory defects during the course of AD development.