A ganglioside-induced toxic soluble Abeta assembly. Its enhanced formation from Abeta bearing the Arctic mutation.
The mechanism underlying plaque-independent neuronal death in Alzheimer disease (AD), which is probably responsible for early cognitive decline in AD patients, remains unclarified. Here, we show that a toxic soluble Abeta assembly (TAbeta) is formed in the presence of liposomes containing GM1 ganglioside more rapidly and to a greater extent from a hereditary variant-type ("Arctic") Abeta than from wild-type Abeta. TAbeta is also formed from soluble Abeta through incubation with natural neuronal membranes prepared from aged mouse brains in a GM1 ganglioside-dependent manner. An oligomer-specific antibody (anti-Oligo) significantly suppresses TAbeta toxicity. Biophysical and structural analyses by atomic force microscopy and size exclusion chromatography revealed that TAbeta is spherical with diameters of 10-20 nm and molecular masses of 200-300 kDa. TAbeta induces neuronal death, which is abrogated by the small interfering RNA-mediated knockdown of nerve growth factor receptors, including TrkA and p75 neurotrophin receptor. Our results suggest that soluble Abeta assemblies, such as TAbeta, can cause plaque-independent neuronal death that favorably occurs in nerve growth factor-dependent neurons in the cholinergic basal forebrain in AD.
Yamamoto
Naoki
N
Department of Alzheimer's Disease Research, National Institute for Longevity Sciences, National Center for Geriatrics and Gerontology, Obu 474-8522, Japan.
Matsubara
Etsuro
E
Maeda
Sumihiro
S
Minagawa
Hirohisa
H
Takashima
Akihiko
A
Maruyama
Wakako
W
Michikawa
Makoto
M
Yanagisawa
Katsuhiko
K
D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D000818:Animals; D016923:Cell Death; D002478:Cells, Cultured; D005677:G(M1) Ganglioside / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D008081:Liposomes; D009154:Mutation; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D034622:RNA Interference; D051381:Rats; D017207:Rats, Sprague-Dawley; D020800:Receptor, Nerve Growth Factor / Q000378:metabolism; D020917:Receptor, trkA / Q000378:metabolism
D016229:Amyloid beta-Peptides; D008081:Liposomes; D020800:Receptor, Nerve Growth Factor; D005677:G(M1) Ganglioside; D020917:Receptor, trkA