Elevated Membrane Cholesterol Disrupts Lysosomal Degradation to Induce β-Amyloid Accumulation
Elevated Membrane Cholesterol Disrupts Lysosomal Degradation to Induce β-Amyloid Accumulation
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膜胆固醇升高破坏溶酶体降解，诱导 β-淀粉样蛋白积累
DOI：
10.1016/j.ajpath.2018.10.011
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发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Kimura Nobuyuki
中科院分区：
文献类型：
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作者：
Takeuchi Shingo;Ueda Naoya;Suzuki Keiko;Shimozawa Nobuhiro;Yasutomi Yasuhiro;Kimura Nobuyuki
早期阿尔茨海默病（AD）患者脑内的内吞膜运输系统发生改变，内吞紊乱影响AD发病机制中的关键分子β-淀粉样蛋白（Aβ）的代谢。2型糖尿病（T2 DM）是AD发病的主要危险因素之一。实验诱导的T2 DM在各种动物模型中增强了AD病理学，这支持了这一联系。自发性T2 DM也会增强Aβ病理学，伴有重度内吞病理学，甚至在非人灵长类动物脑中也是如此。然而，T2 DM如何加速Aβ病理仍不清楚。在此，我们证明了胆固醇代谢相关蛋白水平增加，并且在自发性T2 DM影响的食蟹猴脑中膜胆固醇水平升高。此外，操纵细胞胆固醇的体外研究表明，膜胆固醇升高会破坏溶酶体降解并增强化学诱导的内吞紊乱，导致Aβ在Neuro 2a细胞中大量蓄积。这些结果表明，脑胆固醇代谢的改变可能是T2 DM受影响大脑中Aβ病理学增强的原因，这反过来可能会增加发生AD的风险。
The endocytic membrane trafficking system is altered in the brains of early-stage Alzheimer disease (AD) patients, and endocytic disturbance affects the metabolism of β-amyloid (Aβ) protein, a key molecule in AD pathogenesis. It is widely accepted that type 2 diabetes mellitus (T2DM) is one of the strongest risk factors for development of AD. Supporting this link, experimentally induced T2DM enhances AD pathology in various animal models. Spontaneous T2DM also enhances Aβ pathology with severe endocytic pathology, even in nonhuman primate brains. However, it remains unclear how T2DM accelerates Aβ pathology. Herein, we demonstrate that cholesterol metabolism–related protein levels are increased and that membrane cholesterol level is elevated in spontaneous T2DM-affected cynomolgus monkey brains. Moreover,in vitrostudies that manipulate cellular cholesterol reveal that elevated membrane cholesterol disrupts lysosomal degradation and enhances chemical-induced endocytic disturbance, resulting in great accumulation of Aβ in Neuro2a cells. These findings suggest that an alteration of cerebral cholesterol metabolism may be responsible for augmentation of Aβ pathology in T2DM-affected brains, which, in turn, may increase the risk for developing AD.