A ganglioside-induced toxic soluble Abeta assembly. Its enhanced formation from Abeta bearing the Arctic mutation

J Biol Chem. 2007 Jan 26;282(4):2646-55. doi: 10.1074/jbc.M606202200. Epub 2006 Nov 29.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / metabolism
  • Alzheimer Disease / pathology
  • Amyloid beta-Peptides / genetics
  • Amyloid beta-Peptides / metabolism*
  • Amyloid beta-Peptides / ultrastructure
  • Animals
  • Cell Death
  • Cells, Cultured
  • G(M1) Ganglioside / metabolism*
  • G(M1) Ganglioside / pharmacology
  • Humans
  • Liposomes
  • Mutation
  • Nerve Degeneration / genetics
  • Nerve Degeneration / metabolism
  • Nerve Degeneration / pathology
  • Neurons* / metabolism
  • Neurons* / pathology
  • RNA Interference
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Nerve Growth Factor / metabolism
  • Receptor, trkA / metabolism


  • Amyloid beta-Peptides
  • Liposomes
  • Receptor, Nerve Growth Factor
  • G(M1) Ganglioside
  • Receptor, trkA