下调和上调
凝集素
海马结构
神经退行性变
细胞生物学
生物
化学
蛋白质降解
溶酶体
淀粉样前体蛋白
分子生物学
淀粉样蛋白(真菌学)
阿尔茨海默病
神经科学
细胞凋亡
生物化学
内科学
医学
酶
无机化学
疾病
基因
作者
Yunling Wang,Xike Qin,Hemant K. Paudel
标识
DOI:10.1016/j.nbd.2017.04.003
摘要
Progressive accumulation of amyloid-β peptide (Aβ) in the brain is implicated as the central event in the development of Alzheimer's disease (AD). It is thought that extracellular Aβ triggers toxic signals leading to neurodegeneration. The events downstream of Aβ however are not entirely clear. Clusterin (Apo J) is one of the major risk factors for sporadic form of AD. Clusterin binds to Aβ and prevents Aβ aggregation. In addition, clusterin promotes Aβ degradation and accelerates Aβ clearance from the brain. Clusterin thus protects neurons from Aβ and loss of clusterin level in the brain is implicated as promoting AD pathology. In this study, we found that the level of clusterin protein but not mRNA is reduced in the brains of 3xTg-AD mice. When rat hippocampal primary neurons were treated with Aβ1-42, level of clusterin protein but not mRNA was downregulated. Aβ1-42-induced downregulation of clusterin was blocked by lysosome inhibitors bafilomycin A1 and ammonium chloride. In neurons, Aβ1-42 induced expression of sortilin, a lysosomal sorting protein that targets proteins to lysosome for degradation. In BE(2) M17 human neuroblastoma cells, clusterin bound to sortilin and when sortilin expression was silenced, Aβ1-42-induced clusterin downregulation was almost completely blocked. Our data demonstrate that in neurons, Aβ1-42 promotes lysosomal degradation of clusterin by inducing expression of sortilin and provide a novel mechanism by which Aβ promotes AD pathogenesis.
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