Autophagy failure in Alzheimer's disease--locating the primary defect.
Autophagy failure in Alzheimer's disease--locating the primary defect.
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阿尔茨海默氏病的自噬衰竭 - 将主要缺陷列为。
DOI：
10.1016/j.nbd.2011.01.021
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发表时间：
2011-07
影响因子：
6.1
通讯作者：
Yang, Dun-Sheng
中科院分区：
文献类型：
--
作者：
Nixon, Ralph A.;Yang, Dun-Sheng
关键词：
自噬是细胞器和长寿命蛋白质的主要降解途径，对神经元的存活至关重要。越来越多的证据表明，缺陷性自噬在几种主要的神经退行性疾病，特别是阿尔茨海默病（AD）的发病机制中起作用。已经在AD脑的神经元中鉴定了溶酶体系统的连续异常，包括在最早的疾病阶段的病理性内吞途径反应和自噬的进行性破坏，导致在营养不良的轴突和树突内大量积累不完全消化的底物。在这篇综述中，我们研究了自噬在AD和评估的证据，解决具体的步骤或步骤沿着自噬途径，可能是有缺陷的。目前的证据有力地表明，自噬失败的主要机制是自溶酶体内底物蛋白水解的破坏。在最常见的家族性早发性AD中，突变型早老素1通过阻碍溶酶体蛋白水解直接破坏自噬，而在其他形式的AD中，自噬损伤可能涉及不同的遗传或环境因素。在AD病理学小鼠模型中恢复更正常的溶酶体蛋白水解和自噬效率的尝试已经对神经元功能和认知表现产生了有希望的治疗效果，证明了自噬失败与AD发病机制的相关性以及自噬调节作为治疗策略的潜力。
Autophagy, the major degradative pathway for organelles and long-lived proteins, is essential for the survival of neurons. Mounting evidence has implicated defective autophagy in the pathogenesis of several major neurodegenerative diseases, particularly Alzheimer's disease (AD). A continuum of abnormalities of the lysosomal system has been identified in neurons of the AD brain, including pathological endocytic pathway responses at the very earliest disease stage and a progressive disruption of autophagy leading to the massive buildup of incompletely digested substrates within dystrophic axons and dendrites. In this review, we examine research on autophagy in AD and evaluate evidence addressing the specific step or steps along the autophagy pathway that may be defective. Current evidence strongly points to disruption of substrate proteolysis within autolysosomes for the principal mechanism underlying autophagy failure in AD. In the most common form of familial early onset AD, mutant presenilin 1 disrupts autophagy directly by impeding lysosomal proteolysis while, in other forms of AD, autophagy impairments may involve different genetic or environmental factors. Attempts to restore more normal lysosomal proteolysis and autophagy efficiency in mouse models of AD pathology have yielded promising therapeutic effects on neuronal function and cognitive performance, demonstrating the relevance of autophagy failure to the pathogenesis of AD and the potential of autophagy modulation as a therapeutic strategy.
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神经元中的自噬诱导和自噬体清除：与阿尔茨海默氏病自噬病理学的关系。
影响因子：
5.3
作者：
Boland, Barry;Kumar, Asok;Lee, Sooyeon;Platt, Frances M.;Wegiel, Jerzy;Yu, W. Haung;Nixon, Ralph A.
通讯作者：
Nixon, Ralph A.
影响因子：
56.9
作者：
Cota, D;Proulx, K;Seeley, RJ
通讯作者：
Seeley, RJ
DOI：
10.1016/j.bbalip.2010.05.010
发表时间：
2010-08-01
影响因子：
4.8
作者：
Cossec, Jack-Christophe;Simon, Anne;Potier, Marie-Claude
通讯作者：
Potier, Marie-Claude
影响因子：
2.9
作者：
BENZING, WC;MUFSON, EJ;ARMSTRONG, DM
通讯作者：
ARMSTRONG, DM
影响因子：
15.1
作者：
Bhaskar K;Miller M;Chludzinski A;Herrup K;Zagorski M;Lamb BT
通讯作者：
Lamb BT