ER? promotes A? degradation via the modulation of autophagy.

ABSTRACT: Alzheimer's Disease (AD) is the most common neurodegenerative disorder in the elderly. Beta-amyloid (A?) peptide accumulation is considered as a primary cause of AD pathogenesis, with defective autophagy in patients' brains. Enhanced autophagic activity has been reported to promote A? clearance in vitro and in vivo models. Meanwhile, there is growing evidence that estrogen receptor ? (ER?) is a viable therapeutic target that can ameliorate the pathological features associated with AD. Very little is known about the detailed molecular mechanisms underlying the relationship between ER?, autophagy, and A? degradation in AD. This study aims to uncover whether ER? participates in autophagy and promotes extracellular A?1-42 degradation through the autophagy-lysosome system. Here we find that overexpression of ER? caused autophagic activation as seen by increased microtubule-associated protein 1 light chain 3-II (LC3-II), SQSTM1 (sequestosome 1) degradation, LC3 punctate distribution, autophagosome, and autolysosome accumulation. In addition, we show that ER? could induce autophagy through direct protein-protein interaction with ATG7 (E1-like enzyme). Furthermore, ER?-mediated decrease in A?1-42 was blocked by the autophagy inhibitor chloroquine (CQ) in SH-SY5Y cells and the HEK293T (A?PPsw) model. A?1-42 or CQ induced cytotoxicity was restored by a selective ER? activator diarylpropionitrile (DPN). Collectively, these data indicate that overexpression of ER? exerts a neuroprotective effect through interacting with ATG7 protein and further enhances autophagy-lysosomal activity for A?1-42 clearance at the cellular level.

SUBMITTER: Wei Y 

PROVIDER: S-EPMC6646346 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature