Oxidative stress and lipid peroxidation are upstream of amyloid pathology

• Lipid peroxidation product HNE and oxidant DTDP increase Aβ42/40 ratio in vivo.
• Oxidative stress/HNE induce FAD-like pathogenic conformation of PS1/γ-secretase.
• HNE-adducts on Nct and BACE reduce and enhance secretase activities, respectively.
• HNE may initiate a pathologic cascade by selectively increasing Aβ42 levels.

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 6 h 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.

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