Deletion of M1 muscarinic acetylcholine receptors increases amyloid pathology in vitro and in vivo.
Deletion of M1 muscarinic acetylcholine receptors increases amyloid pathology in vitro and in vivo.
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DOI：
10.1523/jneurosci.6393-09.2010
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发表时间：
2010-03-24
期刊：
影响因子：
--
通讯作者：
Levey AI
中科院分区：
文献类型：
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作者：
Davis AA;Fritz JJ;Wess J;Lah JJ;Levey AI
阿尔茨海默病（AD）是一种渐进性神经系统疾病，其导致痴呆，并且随着人口老龄化而构成重大公共卫生危机。淀粉样前体蛋白（APP）的异常加工强烈地暗示为AD病理生理学中的近端事件，但是调节大脑中APP加工的神经化学信号尚未完全理解。已证明毒蕈碱乙酰胆碱受体（mAChR）的激活会影响APP加工和AD病理，但对特定mAChR亚型的作用知之甚少。在这项研究中，我们使用M1 mAChR基因敲除小鼠（M1 KO）分离的M1 mAChR对APP加工在初级神经元和淀粉样蛋白病理学的发展在AD的转基因小鼠模型的影响。我们证明，M1 mAChRs的缺失增加了神经元中淀粉样APP的加工，这可以通过神经保护性APP胞外域APP α的激动剂调节脱落减少和毒性Aβ肽的产生增加来证明。M1 mAChR在M1 KO背景下的表达挽救了这种表型，表明M1 mAChR足以调节非淀粉样蛋白生成性APP加工。在APPSwe/Ind转基因小鼠中，M1 mAChRs的缺失导致脑Aβ1-40水平升高和淀粉样斑块病理学的更大积累。对APPSwe/Ind脑组织中APP代谢物的分析表明，M1 mAChR的丢失增加了淀粉样APP加工。这些结果表明，M1 mAChR是一个重要的调节剂的淀粉样蛋白在大脑中，并提供了强有力的支持，针对M1 mAChR作为一种治疗候选人在AD。
Alzheimer's disease (AD) is a progressive neurological disorder that causes dementia and poses a major public health crisis as the population ages. Aberrant processing of the amyloid precursor protein (APP) is strongly implicated as a proximal event in AD pathophysiology, but the neurochemical signals that regulate APP processing in the brain are not completely understood. Activation of muscarinic acetylcholine receptors (mAChRs) has been shown to affect APP processing and AD pathology, but less is known about the roles of specific mAChR subtypes. In this study, we used M1 mAChR knockout mice (M1KO) to isolate the effects of the M1 mAChR on APP processing in primary neurons and on the development of amyloid pathology in a transgenic mouse model of AD. We demonstrate that the loss of M1 mAChRs increases amyloidogenic APP processing in neurons, as evidenced by decreased agonist-regulated shedding of the neuroprotective APP ectodomain APPsα and increased production of toxic Aβ peptides. Expression of M1 mAChRs on the M1KO background rescued this phenotype, indicating that M1 mAChRs are sufficient to modulate non-amyloidogenic APP processing. In APPSwe/Ind transgenic mice, the loss of M1 mAChRs resulted in increased levels of brain Aβ1-40 and greater accumulation of amyloid plaque pathology. Analysis of APP metabolites in APPSwe/Ind brain tissue indicates that the loss of M1 mAChRs increases amyloidogenic APP processing. These results indicate that the M1 mAChR is an important regulator of amyloidogenesis in the brain and provide strong support for targeting the M1 mAChR as a therapeutic candidate in AD.