Oxidative stress and lipid peroxidation are upstream of amyloid pathology

NEUROBIOLOGY OF DISEASE

卷:84

Article

Arimon, Muriel¹  Takeda, Shuko¹  Post, Kathryn L.¹  Svirsky, Sarah¹  Hyman, Bradley T.¹  Berezovska, Oksana¹ 

[1] Harvard Univ, Sch Med, Massachusetts Gen Hosp, MassGen Inst Neurodegenerat Dis,Dept Neurol, Charlestown, MA 02129 USA

关键词: Oxidative stress;    Lipid peroxidation;    Alzheimer's disease;    Microdialysis;    Amyloid beta;    gamma-Secretase;    Presenilin;    4-Hydroxynonenal;   

DOI  :  10.1016/j.nbd.2015.06.013

来源: Elsevier

【 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.

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