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Neurobiol Dis. 2015 Dec;84:109-19. doi: 10.1016/j.nbd.2015.06.013. Epub 2015 Jun 21.

Oxidative stress and lipid peroxidation are upstream of amyloid pathology.

Author information

1
MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, CNY 114, 16th Street, Charlestown 02129, MA, USA.
2
MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, CNY 114, 16th Street, Charlestown 02129, MA, USA. Electronic address: OBerezovska@partners.org.

Abstract

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-β42 levels and elevated amyloid-β42/40 ratio in the interstitial fluid within 6h of direct infusion of oxidizing agents into the hippocampus of living and awake wild type mice. The increase in the amyloid-β42/40 ratio correlated with the pathogenic conformational change of the amyloid precursor protein-cleaving enzyme, presenilin1/γ-secretase. Furthermore, we found that the product of lipid peroxidation 4-hydroxynonenal, binds to both nicastrin and BACE, differentially affecting γ- and β-secretase activity, respectively. The present study demonstrates a direct cause-and-effect correlation between oxidative stress and altered amyloid-β production, and provides a molecular mechanism by which naturally occurring product of lipid peroxidation may trigger generation of toxic amyloid-β42 species.

KEYWORDS:

4-Hydroxynonenal; Alzheimer's disease; Amyloid beta; Lipid peroxidation; Microdialysis; Oxidative stress; Presenilin; γ-Secretase

PMID:
26102023
PMCID:
PMC4684986
DOI:
10.1016/j.nbd.2015.06.013
[Indexed for MEDLINE]
Free PMC Article

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