A ganglioside-induced toxic soluble Aβ assembly: Its enhanced formation from Aβ bearing the arctic mutation

Naoki Yamamoto, Etsuro Matsubara, Sumihiro Maeda, Hirohisa Minagawa, Akihiko Takashima, Wakako Maruyama, Makoto Michikawa, Katsuhiko Yanagisawa

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59 Citations (Scopus)

Abstract

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 Aβ assembly (TAβ) is formed in the presence of liposomes containing GM1 ganglioside more rapidly and to a greater extent from a hereditary variant-type ("Arctic") Aβ than from wild-type Aβ. TAβ is also formed from soluble Aβ 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 TAβ toxicity. Biophysical and structural analyses by atomic force microscopy and size exclusion chromatography revealed that TAβ is spherical with diameters of 10-20 nm and molecular masses of 200-300 kDa. TAβ 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 Aβ assemblies, such as TAβ, can cause plaque-independent neuronal death that favorably occurs in nerve growth factor-dependent neurons in the cholinergic basal forebrain in AD.

Original languageEnglish
Pages (from-to)2646-2655
Number of pages10
JournalJournal of Biological Chemistry
Volume282
Issue number4
DOIs
Publication statusPublished - 2007 Jan 26
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Yamamoto, N., Matsubara, E., Maeda, S., Minagawa, H., Takashima, A., Maruyama, W., Michikawa, M., & Yanagisawa, K. (2007). A ganglioside-induced toxic soluble Aβ assembly: Its enhanced formation from Aβ bearing the arctic mutation. Journal of Biological Chemistry, 282(4), 2646-2655. https://doi.org/10.1074/jbc.M606202200