Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, Hubei, PR China.
Cell Death Dis. 2019 Jul 22;10(8):565. doi: 10.1038/s41419-019-1786-8.
Alzheimer's Disease (AD) is the most common neurodegenerative disorder in the elderly. Beta-amyloid (Aβ) 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 Aβ clearance in vitro and in vivo models. Meanwhile, there is growing evidence that estrogen receptor β (ERβ) 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 ERβ, autophagy, and Aβ degradation in AD. This study aims to uncover whether ERβ participates in autophagy and promotes extracellular Aβ degradation through the autophagy-lysosome system. Here we find that overexpression of ERβ 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 ERβ could induce autophagy through direct protein-protein interaction with ATG7 (E1-like enzyme). Furthermore, ERβ-mediated decrease in Aβ was blocked by the autophagy inhibitor chloroquine (CQ) in SH-SY5Y cells and the HEK293T (AβPPsw) model. Aβ or CQ induced cytotoxicity was restored by a selective ERβ activator diarylpropionitrile (DPN). Collectively, these data indicate that overexpression of ERβ exerts a neuroprotective effect through interacting with ATG7 protein and further enhances autophagy-lysosomal activity for Aβ clearance at the cellular level.
阿尔茨海默病（AD）是老年人中最常见的神经退行性疾病。β-淀粉样肽（Aβ）肽积累被认为是 AD 发病机制的主要原因，患者大脑中的自噬作用有缺陷。已有报道称，增强自噬活性可促进体外和体内模型中 Aβ的清除。同时，越来越多的证据表明，雌激素受体β（ERβ）是一种可行的治疗靶点，可改善与 AD 相关的病理特征。关于 ERβ、自噬和 Aβ降解在 AD 中的关系的详细分子机制知之甚少。本研究旨在揭示 ERβ 是否通过自噬溶酶体系统参与自噬并促进细胞外 Aβ的降解。在这里，我们发现 ERβ 的过表达导致自噬的激活，表现为微管相关蛋白 1 轻链 3-II（LC3-II）增加、SQSTM1（自噬体 1）降解、LC3 点状分布、自噬体和自噬溶酶体积累。此外，我们表明 ERβ 可以通过与 ATG7（E1 样酶）的直接蛋白-蛋白相互作用诱导自噬。此外，在 SH-SY5Y 细胞和 HEK293T（AβPPsw）模型中，自噬抑制剂氯喹（CQ）阻断了 ERβ 介导的 Aβ减少。用选择性 ERβ 激活剂二芳基丙腈（DPN）可恢复 Aβ或 CQ 诱导的细胞毒性。总之，这些数据表明，ERβ 的过表达通过与 ATG7 蛋白相互作用发挥神经保护作用，并进一步增强自噬溶酶体活性，以在细胞水平清除 Aβ。
