Effect of APOE genotype and Alzheimer pathology formation on synaptic membrane lipids of human brains (598.2)

Abstract

APOE genotype has great impact on the development of Alzheimer’s disease (AD), i.e., ε4 allele accelerates whereas ε2 allele suppresses the development of AD; however, how APOE genotype affects AD development remains unclear. On the basis of the previous finding that the assembly of the amyloid ß‐protein (Aß) into fibrils in the brain, an early and invariable pathological feature of AD, depends on the lipid environment of membrane, we examined whether lipid composition of synaptic plasma membrane, which is an initial site of amyloid deposition, of human brain varies in an APOE genotype dependent manner. Levels of cholesterol and ganglioside in synaptic plasma membranes prepared from human cortices of aged individuals were examined using Amplex‐Red cholesterol assay kit and by LC‐MS analyses, respectively. In the comparison between amyloid‐free ε2/ε3 and ε3/ε3 brains, the levels of cholesterol were significantly lower in the subjects carrying ε2 allele. Alternatively, the presence of AD pathology substantially decreased the levels of cholesterol in the subjects carrying ε3 allele. This study suggests that ε2 allele suppresses AD development by keeping cholesterol in synaptic membranes under a certain level, which is prerequisite for the initiation of Aß assembly into fibrils.