Synaptotoxic amyloid-β oligomers: A molecular basis for the cause, diagnosis, and treatment of Alzheimer's disease?

William L. Klein*

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

114 Scopus citations

Abstract

The oligomer hypothesis for Alzheimer's disease (AD) was introduced in 1998. It was based on evidence that oligomers could exist free of amyloid fibrils, that fibril-free oligomer solutions rapidly inhibited long term potentiation, and that oligomers ultimately caused a highly selective nerve cell death. Fibrils no longer were the only toxins made by amyloid-β (Aβ), and likely not the most important ones. Oligomers provided a new basis for instigating AD. Since introduction of the hypothesis, more than 1,500 articles on oligomers have been published. Articles for this review were selected for contributions to oligomer theory at three different levels. The first set demonstrated new aspects of oligomer pathobiology in cell models, showing that exposure of neurons to oligomers is sufficient to cause key features of AD neuropathology. The second set confirmed the relationship between oligomers and salient AD neuropathology in animal models, consistent with other in vivo studies that overall have substantiated cell-based discoveries. The third set developed strategies for therapeutic targeting of oligomers, introducing both small molecule and antibody-based approaches. These and related findings from many groups have helped establish oligomers as central to the mechanism of AD pathogenesis. Comprising a ligand-based attack on specific synapses, the action of toxic oligomers gives a molecular basis to account for key features of AD neuropathology and to explain why early disease targets memory. Although there still is no effective treatment for AD, insights over the past five years raise hopes that new approaches targeting Aβ oligomers could finally bring disease-modifying therapeutics.

Original languageEnglish (US)
Pages (from-to)S49-S65
JournalJournal of Alzheimer's Disease
Volume33
Issue numberSUPPL. 1
DOIs
StatePublished - Jan 1 2013

Keywords

  • Alzheimer's disease pathogenesis
  • amyloid-β oligomers
  • animal models
  • biomarkers
  • cellular mechanisms
  • vaccines

ASJC Scopus subject areas

  • Neuroscience(all)
  • Clinical Psychology
  • Geriatrics and Gerontology
  • Psychiatry and Mental health

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