Accelerated Aβ aggregation in the presence of GM1-ganglioside-accumulated synaptosomes of aged apoE4-knock-in mouse brain

Aging and apolipoprotein E4 (apoE4) expression are strong risk factors for the development of Alzheimer's disease (AD); however, their pathological roles remain to be clarified. In the process of AD development, the conversion of the nontoxic amyloid-protein (A) monomer to its toxic aggregates is a fundamental process. We previously hypothesized that A aggregation is accelerated through the generation of GM1 ganglioside (GM1)-bound A which acts as a seed for A fibril formation. Here we report that GM1 level in detergent-resistant membrane microdomains (DRMs) of synaptosomes increased with age and that this increase was significantly pronounced in the apoE4- than the apoE3-knock-in mouse brain. Furthermore, we show that A aggregation is markedly accelerated in the presence of the synaptosomes of the aged apoE4-knock-in mouse brain. These observations suggest that aging and apoE4 expression cooperatively accelerate A aggregation in the brain through an increase in the level of GM1 in neuronal membranes. (C) 2004 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.