Oxidative stress and lipid peroxidation are upstream of amyloid pathology

被引:119
作者
Arimon, Muriel [1 ]
Takeda, Shuko [1 ]
Post, Kathryn L. [1 ]
Svirsky, Sarah [1 ]
Hyman, Bradley T. [1 ]
Berezovska, Oksana [1 ]
机构
[1] Harvard Univ, Sch Med, Massachusetts Gen Hosp, MassGen Inst Neurodegenerat Dis,Dept Neurol, Charlestown, MA 02129 USA
基金
美国国家卫生研究院;
关键词
Oxidative stress; Lipid peroxidation; Alzheimer's disease; Microdialysis; Amyloid beta; gamma-Secretase; Presenilin; 4-Hydroxynonenal; FAMILIAL ALZHEIMERS-DISEASE; MILD COGNITIVE IMPAIRMENT; GAMMA-SECRETASE; BETA-PEPTIDE; IN-VIVO; PROTEOMIC IDENTIFICATION; PRESENILIN MUTATIONS; TALKING POINT; MOUSE MODEL; BRAIN;
D O I
10.1016/j.nbd.2015.06.013
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Oxidative stress is a common feature of the aging process and of many neurodegenerative disorders, including Alzheimer's disease. Understanding the direct causative relationship between oxidative stress and amyloid pathology, and determining the underlying molecular mechanisms is crucial for the development of more effective therapeutics for the disease. By employing microdialysis technique, we report local increase in the amyloid-beta(42) levels and elevated amyloid-beta(42/40) ratio in the interstitial fluid within 6 h of direct infusion of oxidizing agents into the hippocampus of living and awake wild type mice. The increase in the amyloid-beta(42/40) ratio correlated with the pathogenic conformational change of the amyloid precursor protein-cleaving enzyme, presenilin1/gamma-secretase. Furthermore, we found that the product of lipid peroxidation 4-hydroxynonenal, binds to both nicastrin and BACE, differentially affecting gamma- and beta-secretase activity, respectively. The present study demonstrates a direct cause-and-effect correlation between oxidative stress and altered amyloid-beta production, and provides a molecular mechanism by which naturally occurring product of lipid peroxidation may trigger generation of toxic amyloid-beta(42) species. (C) 2015 Elsevier Inc All rights reserved.
引用
收藏
页码:109 / 119
页数:11
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