Analysis of underlying mechanism to develop Alzheimer's disease

γ -分泌酶在大脑中从β淀粉样蛋白（Ab）前体蛋白产生β淀粉样蛋白（Ab），这对阿尔茨海默病（AD）的发病机制至关重要。内质网（ER）应激产生未折叠蛋白，未折叠蛋白反应（UPR）对未折叠蛋白进行加工。肥胖和糖尿病是AD的危险因素，其发病机制与内质网应激有关。然而，内质网应激是否参与AD的发展尚不清楚。在本研究中，我发现内质网应激激活γ -分泌酶，通过诱导活化转录因子4 （ATF4）导致Ab增加。槲皮素可诱导生长阻滞和DNA损伤诱导基因（GADD）34抑制体外Ab的分泌。此外，我们发现AD模型小鼠APP23的脑组织中磷酸化的eIF2alpha和ATF4增加。这些结果表明，内质网应激信号可能在AD患者的大脑中受到干扰。

Gamma-secretase produces amyloid-beta (Ab) in the brain from Ab precursor protein, which is critical for tha pathogenesis of Alzheimer's disease (AD). The endoplasmic reticulum (ER) stress causes unfolded proteins, which are processed by unfolded protein response (UPR). Pathogenesis of obesity and diabetes, which are risk factors for AD, is related to ER stress. However, whether ER stress is engaged in the development of AD remains obscure. In this research, I showed that ER stress activated gamma-secretase, leading to augmentation of Ab through induction of activating transcription factor 4 (ATF4). Ab secretion was repressed in vitro by quercetin, which induced the growth arrest and DNA damaged-inducible gene (GADD)34. In addition, we found that phosphorylated eIF2alpha and ATF4 were increased in the brain of AD model mice APP23. These results suggest that ER stress signaling may be disturbed in the brain of AD.