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Current Alzheimer Research

Editor-in-Chief

ISSN (Print): 1567-2050
ISSN (Online): 1875-5828

Lipid Rafts Mediate Amyloid-Induced Calcium Dyshomeostasis and Oxidative Stress in Alzheimer’s Disease

Author(s): Elisa Evangelisti, Daniel Wright, Mariagioia Zampagni, Roberta Cascella, Claudia Fiorillo, Silvia Bagnoli, Annalisa Relini, Daniela Nichino, Tania Scartabelli, Benedetta Nacmias, Sandro Sorbi and Cristina Cecchi

Volume 10 , Issue 2 , 2013

Page: [143 - 153] Pages: 11

DOI: 10.2174/1567205011310020004

Price: $65

Abstract

Several lines of evidence suggest that the initial events of amyloid-β peptide (Aβ) oligomerization and deposition in Alzheimer’s disease (AD) involve the interaction of soluble oligomers with neuronal membranes. In this study, we show that Aβ42 oligomers are recruited to lipid rafts, which are ordered membrane microdomains rich in cholesterol and gangliosides, resulting in lipid peroxidation, Ca2+ dyshomeostasis and membrane permeabilization in primary fibroblasts from familial AD patients (FAD) bearing APPVal717Ile, PS-1Leu392Val or PS-1Met146Leu gene mutations. Moreover, the presence of significantly higher levels of lipid peroxidation correlated with greater structural modification in detergent resistant domains (DRMs) isolated from APP and PS-1 fibroblasts, compared to WT fibroblasts from healthy subjects. Modulation of raft GM1, including modest depletion of GM1 content and interference with GM1 exposure or negative charge, precluded the interaction of amyloid aggregates with the plasma membrane and the resulting cell damage in FAD fibroblasts and rat brains cortical neurons. These findings suggest a specific role for raft domains as primary mediators of amyloid toxicity in AD neurons.

Keywords: Alzheimer’s disease fibroblasts, amyloid aggregate toxicity, calcium dysregulation, membrane GM1, oxidative stress, primary cortical neurons


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