Influence of APOE genotype and the presence of Alzheimer's pathology on synaptic membrane lipids of human brains.
The APOE genotype is the major risk factor for Alzheimer's disease (AD); however, it remains unclarified how the ε4 allele accelerates whereas the ε2 allele suppresses AD development, compared with the more common ε3 allele. On the basis of the previous finding that the assembly of the amyloid-β protein (Aβ) into fibrils in the brain, an early and invariable pathological feature of AD, depends on the lipid environment, we determined the levels of synaptic membrane lipids in aged individuals of different APOE genotypes. In the comparison between amyloid-free ε2/ε3 and ε3/ε3 brains, the presence of the ε2 allele significantly decreased the level of cholesterol. Alternatively, in the comparison among ε3/ε3 brains, the presence of AD pathology substantially decreased the levels of cholesterol. This study suggests that the ε2 allele suppresses the initiation of AD development by lowering the cholesterol levels in synaptic membranes.
Department of Drug Discovery, Center for Development of Advanced Medicine for Dementia, National Center for Geriatrics and Gerontology, Obu, Japan.
Naoto
N
Oikawa
Hiroyuki
H
Hatsuta
Shigeo
S
Murayama
Akemi
A
Suzuki
Katsuhiko
K
Yanagisawa
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D001057:Apolipoproteins E / Q000235:genetics*; D001921:Brain / Q000473:pathology*; D002784:Cholesterol / Q000378:metabolism; D005260:Female; D005732:Gangliosides / Q000378:metabolism; D005838:Genotype; D006801:Humans; D008055:Lipids / Q000235:genetics; D008297:Male; D013570:Synaptic Membranes / Q000235:genetics / Q000473:pathology / Q000648:ultrastructure; D013574:Synaptosomes / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D001057:Apolipoproteins E; D005732:Gangliosides; D008055:Lipids; D002784:Cholesterol
Alzheimer's disease; cholesterol; ganglioside; microdomain; synaptic plasma membrane