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首页> 外文期刊>Neuron >ADAM10 Missense Mutations Potentiate β-Amyloid Accumulation by Impairing Prodomain Chaperone Function
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ADAM10 Missense Mutations Potentiate β-Amyloid Accumulation by Impairing Prodomain Chaperone Function

机译：ADAM10错义突变通过削弱前域伴侣功能增强β-淀粉样蛋白的积累。

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摘要

The generation of Aβ, the main component of senile plaques in Alzheimer's disease (AD), is precluded by α-secretase cleavage within the Aβ domain of the amyloid precursor protein (APP). We identified two rare mutations (Q170H and R181G) in the prodomain of the metalloprotease, ADAM10, that cosegregate with late-onset AD (LOAD). Here, we addressed the pathogenicity of these mutations in transgenic mice expressing human ADAM10 in brain. In Tg2576 AD mice, both mutations attenuated α-secretase activity of ADAM10 and shifted APP processing toward β-secretase-mediated cleavage, while enhancing Aβ plaque load and reactive gliosis. We also demonstrated ADAM10 expression potentiates adult hippocampal neurogenesis, which is reduced by the LOAD mutations. Mechanistically, both LOAD mutations impaired the molecular chaperone activity of ADAM10 prodomain. Collectively, these findings suggest that diminished α-secretase activity, owing to LOAD ADAM10 prodomain mutations, leads to AD-related pathology, strongly supporting ADAM10 as a promising therapeutic target for this devastating disease.
机译：淀粉样前体蛋白（APP）的Aβ结构域内的α分泌酶裂解可阻止阿尔茨海默氏病（AD）中老年斑的主要成分Aβ的产生。我们在金属蛋白酶ADAM10的前结构域中发现了两个罕见突变（Q170H和R181G），它们与晚期AD（LOAD）共分离。在这里，我们解决了在大脑中表达人ADAM10的转基因小鼠中这些突变的致病性。在Tg2576 AD小鼠中，两个突变均减弱了ADAM10的α-分泌酶活性，并使APP处理朝着β-分泌酶介导的裂解方向移动，同时增强了Aβ斑块负荷和反应性神经胶质增生。我们还证明了ADAM10的表达增强了成年海马神经发生，而LOAD突变可降低其表达。从机理上讲，两个LOAD突变均损害ADAM10前结构域的分子伴侣活性。总体而言，这些发现表明，由于LOAD ADAM10前结构域突变而导致的α-分泌酶活性降低，导致了AD相关的病理学，强烈支持ADAM10作为这一毁灭性疾病的有希望的治疗靶标。

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