Oxidative stress and lipid peroxidation are upstream of amyloid pathology

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.

Intraneuronal Amylin Deposition, Peroxidative Membrane Injury and Increased IL-1β Synthesis in Brains of Alzheimer’s Disease Patients with Type-2 Diabetes and in Diabetic HIP Rats

“…Thus, amylin dyshomeostasis induces systemic peroxidative injury independent of hyperglycemia. The link of amylin dyshomeostasis with increased lipid peroxidation may be of further relevance via its role in enzyme activities, cell signaling and gene expression [31]. …”

An Extract from Shrimp Processing By-Products Protects SH-SY5Y Cells from Neurotoxicity Induced by Aβ25–35

“…Previous studies demonstrated that toxicity of Aβ 25–35 in models of neurodegenerative diseases in vitro and in vivo was associated with the enhancement of ROS and NO liberation and oxidative damage [37,38,39,40,41], which up-regulated redox-sensitive transcription factors such as NF-κB, an important factor responsible for oxidative and inflammatory reactions in AD [42]. In agreement with these studies, Aβ 25–35 increased the ROS and NO production from SH-SY5Y cells in the present study.…”

In vivoimaging of prodromal hippocampus CA1 subfield oxidative stress in models of Alzheimer disease and Angelman syndrome

“…An essential brain region involved in encoding spatial memories is the CA1 subfield of the mid-and posterior hippocampus (human) or dorsal CA1 (CA1d) in rodents (3,4). A leading hypothesis in the field based on ex vivo measurements is that hippocampus oxidative stress plays a pathogenic role in spatial disorientation (2,(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16). This hypothesis has developed on the basis of studies in postmortem tissue of oxidative damage biomarkers, such as buildup of the polyunsaturated fatty acid oxidation product 4-hydroxynonenal (HNE) (17,18).…”