A seed for Alzheimer amyloid in the brain.
A fundamental question about the early pathogenesis of Alzheimer's disease (AD) concerns how toxic aggregates of amyloid beta protein (Abeta) are formed from its nontoxic soluble form. We hypothesized previously that GM1 ganglioside-bound Abeta (GAbeta) is involved in the process. We now examined this possibility using a novel monoclonal antibody raised against GAbeta purified from an AD brain. Here, we report that GAbeta has a conformation distinct from that of soluble Abeta and initiates Abeta aggregation by acting as a seed. Furthermore, GAbeta generation in the brain was validated by both immunohistochemical and immunoprecipitation studies. These results imply a mechanism underlying the onset of AD and suggest that an endogenous seed can be a target of therapeutic strategy.
Hayashi
Hideki
H
Department of Dementia Research, National Institute for Longevity Sciences, Obu 474-8522, Japan.
Kimura
Nobuyuki
N
Yamaguchi
Haruyasu
H
Hasegawa
Kazuhiro
K
Yokoseki
Tatsuki
T
Shibata
Masao
M
Yamamoto
Naoki
N
Michikawa
Makoto
M
Yoshikawa
Yasuhiro
Y
Terao
Keiji
K
Matsuzaki
Katsumi
K
Lemere
Cynthia A
CA
Selkoe
Dennis J
DJ
Naiki
Hironobu
H
Yanagisawa
Katsuhiko
K
D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D000682:Amyloid / Q000096:biosynthesis* / Q000737:chemistry; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D000818:Animals; D000918:Antibody Specificity; D052160:Benzothiazoles; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D001923:Brain Chemistry; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D005677:G(M1) Ganglioside / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008081:Liposomes / Q000737:chemistry; D008252:Macaca fascicularis; D046911:Macromolecular Substances; D016253:Microscopy, Immunoelectron; D008875:Middle Aged; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D013844:Thiazoles / Q000737:chemistry / Q000378:metabolism; D013997:Time Factors
D000682:Amyloid; D016229:Amyloid beta-Peptides; D052160:Benzothiazoles; D008081:Liposomes; D046911:Macromolecular Substances; D010446:Peptide Fragments; D013844:Thiazoles; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); C009462:thioflavin T; D005677:G(M1) Ganglioside