Disruption of BAG3-mediated BACE1 stabilization alleviates neuropathology and memory deficits in a mouse model of Alzheimer's disease.

ABSTRACT: β-Site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1) is the rate-limiting enzyme for amyloid-β (Aβ) generation and is considered promising drug target for Alzheimer's disease (AD). The co-chaperone BAG3 (Bcl-2-associated athanogene 3) plays an important role in maintaining intracellular protein homeostasis by regulating heat shock protein 70 (HSP70). Here, we reported that BAG3 expression was significantly elevated in AD. It interacted with and stabilized BACE1 by delaying its degradation through ubiquitin-proteasome and autophagy-lysosomal pathways. BAG3^E455K and BAG3^R480A mutations reduced their interaction with BACE1. SPOT peptide arrays revealed that BACE1 carboxyl-terminal peptide fragments bound to the RQ domain of BAG3. This interaction can be disru

SUBMITTER: Xia L 

PROVIDER: S-EPMC12101485 | biostudies-literature | 2025 May

REPOSITORIES: biostudies-literature