title: Accelerated Abeta aggregation in the presence of GM1-ganglioside-accumulated synaptosomes of aged apoE4-knock-in mouse brain.
abstract: 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 beta-protein (Abeta) monomer to its toxic aggregates is a fundamental process. We previously hypothesized that Abeta aggregation is accelerated through the generation of GM1 ganglioside (GM1)-bound Abeta which acts as a seed for Abeta 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 Abeta 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 Abeta aggregation in the brain through an increase in the level of GM1 in neuronal membranes.
authors.affiliation: Department of Alzheimer's Disease Research, National Institute for Longevity Sciences, National Center for Geriatrics and Gerontology, 36-3 Gengo, Morioka, Obu 474-8522, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Yamamoto
authors.forename: Urule
authors.initials: U
authors.lastname: Igbabvoa
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Shimada
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Ohno-Iwashita
authors.forename: Mariko
authors.initials: M
authors.lastname: Kobayashi
authors.forename: W Gibson
authors.initials: WG
authors.lastname: Wood
authors.forename: Shinobu C
authors.initials: SC
authors.lastname: Fujita
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Yanagisawa
mesh_terms: D000375:Aging; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D053327:Apolipoprotein E4; D001057:Apolipoproteins E / Q000235:genetics* / Q000378:metabolism; D001921:Brain / Q000254:growth & development / Q000378:metabolism*; D005677:G(M1) Ganglioside / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D013574:Synaptosomes / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D053327:Apolipoprotein E4; D001057:Apolipoproteins E; D005677:G(M1) Ganglioside