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: Chapter in Book/Report/Conference proceedingChapter

Abstract

The oligomer hypothesis for Alzheimer's disease (AD)was introduced in 1998. Itwas 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)
Title of host publicationAlzheimer's Disease
Subtitle of host publicationAdvances for a New Century
PublisherIOS Press
Pages49-65
Number of pages17
ISBN (Electronic)9781614991540
ISBN (Print)9781614991533
DOIs
StatePublished - Feb 15 2013

Keywords

  • Alzheimer's disease pathogenesis
  • Amyloid-β oligomers
  • Animal models
  • Biomarkers
  • Cellular mechanisms
  • Vaccines

ASJC Scopus subject areas

  • Medicine(all)
  • Neuroscience(all)

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