Abstract
The β-secretase enzyme BACE1 (β-site amyloid precursor protein-cleaving enzyme 1), which initiates amyloid-β (Aβ) 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 Aβ accumulation and related memory impairments become less sensitive to rescue by BACE1+/− reduction. Haploinsufficiency lowered BACE1 expression by ∼50% in 5XFAD mice regardless of age in concordance with reduction in gene copy number. However, profound Aβ 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 AD progression, in 5XFAD mice. Our investigation revealed that PERK (PKR-endoplasmic reticulum-related kinase)-dependent activation of eIF2α (eukaryotic translation initiation factor-2α) 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 Aβ-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 Aβ accumulation and rescue memory defects during the course of AD development.
Highlights
The b-secretase called BACE1 (b-site amyloid precursor protein-cleaving enzyme 1) is responsible for initiating the generation of amyloid-b (Ab) peptides.[1]
A growing body of evidence has demonstrated that BACE1 has a number of substrates besides amyloid precursor protein (APP),[4,5,6,7] and that endogenous levels of Ab may be required for physiological functions including learning and memory.[47,48]
We found that the benefits associated with BACE1 haploinsufficiency dramatically decline in 5XFAD mice with advanced age, because of its inability to prevent deleterious mechanisms leading to accelerated Ab overproduction and compromised Ab clearance
Summary
The b-secretase called BACE1 (b-site amyloid precursor protein-cleaving enzyme 1) is responsible for initiating the generation of amyloid-b (Ab) peptides.[1]. The beneficial outcomes associated with BACE1 haploinsufficiency decline with age or the progression of disease in APP transgenic mice.[11,22,25,26] the most recent studies of BACE1 inhibitors successfully show cognitive improvements concomitant with cerebral Ab reduction following systemic administration in relatively earlier stages of APP mice, the decrease in efficacy is noted with advanced age.[28,29] For preclinical validation of BACE1-inhibiting therapeutic approaches, it is imperative to determine the mechanisms that may lessen benefits from genetic or pharmacologic b-secretase suppression during the course of AD development
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
