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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