Large soluble oligomers of amyloid β-protein from alzheimer brain are far less neuroactive than the smaller oligomers to which they dissociate

Ting Yang, Shaomin Li, Huixin Xu, Dominic M. Walsh, Dennis J. Selkoe

Research output: Contribution to journalArticle

116 Scopus citations

Abstract

Soluble oligomers of amyloid β -protein (oAβ) isolated from the brains of Alzheimer’s disease (AD) patients have been shown experimentally (in the absence of amyloid plaques) to impair hippocampal synaptic plasticity, decrease synapses, induce tau hyperphosphorylation and neuritic dystrophy, activate microglial inflammation, and impair memory in normal adult rodents. Nevertheless, there has been controversy about what types of oligomers actually confer these AD-like phenotypes. Here, we show that the vast majority of soluble Aβ species obtained from brains of humans who died with confirmed AD elute at high molecular weight (HMW) on nondenaturing size-exclusion chromatography. These species have little or no cytotoxic activity in several bioassays. However, incubation ofHMWoAβ in mildly alkaline buffer led to their quantitative dissociation into low molecular weight oligomers (8 –70 kDa), and these were now far more bioactive: they impaired hippocampal LTP, decreased neuronal levels of β2-adrenergic receptors, and activated microglia in wt mice in vivo. Thus, most soluble Aβ assemblies in AD cortex are large and inactive but under certain circumstances can dissociate into smaller, highly bioactive species. Insoluble amyloid plaques likely sequester solubleHMWoligomers, limiting their potential to dissociate. Weconclude that conditions that destabilizeHMWoligomers or retard the sequestration of their smaller,morebioactive components are important drivers of Aβ toxicity. Selectively targeting these small, cytotoxic forms should be therapeutically beneficial.

Original languageEnglish (US)
Pages (from-to)152-163
Number of pages12
JournalJournal of Neuroscience
Volume37
Issue number1
DOIs
StatePublished - Jan 4 2017
Externally publishedYes

Keywords

  • Alzheimer’s
  • Aβ aggregation
  • Long-term potentiation
  • Microglia activation
  • Size-exclusion chromatography
  • β2-adrenergic receptor

ASJC Scopus subject areas

  • Neuroscience(all)

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