Differentiating Alzheimer disease-associated aggregates with small molecules.

Methods Development

Abstract

Alzheimer disease is diagnosed postmortem by the density and spatial distribution of beta-amyloid plaques and tau-bearing neurofibrillary tangles. The major protein component of each lesion adopts cross-beta-sheet conformation capable of binding small molecules with submicromolar affinity. In many cases, however, Alzheimer pathology overlaps with Lewy body disease, characterized by the accumulation of a third cross-beta-sheet forming protein, alpha-synuclein. To determine the feasibility of distinguishing tau aggregates from beta-amyloid and alpha-synuclein aggregates with small molecule probes, a library containing 72,455 small molecules was screened for antagonists of tau-aggregate-mediated changes in Thioflavin S fluorescence, followed by secondary screens to distinguish the relative affinity for each substrate protein. Results showed that >10-fold binding selectivity among substrates could be achieved, with molecules selective for tau aggregates containing at least three aromatic or rigid moieties connected by two rotatable bonds.

Authors

Honson, Nicolette S; Johnson, Ronald L; Huang, Wenwei; Inglese, James; Austin, Christopher; Kuret, Jeff;

Keywords

  • Alzheimer Disease/ diagnosis
  • Alzheimer Disease/ metabolism
  • Amyloid beta-Peptides/ metabolism
  • Dose-Response Relationship, Drug
  • Fluorescent Dyes/ chemistry
  • Fluorescent Dyes/ pharmacokinetics
  • Humans
  • Mass Spectrometry/ methods
  • Neurofibrillary Tangles/ metabolism
  • Peptide Library
  • Plaque, Amyloid/ metabolism
  • Thiazines/ chemistry
  • Thiazines/ pharmacokinetics
  • Thiazoles/ chemistry
  • Thiazoles/ pharmacokinetics
  • alpha-Synuclein/ metabolism
  • tau Proteins/ metabolism

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