High throughput screens for the identification of compounds that alter the accumulation of the Alzheimer's amyloid beta peptide (Abeta).

Therapeutic Approaches

Abstract

Evidence gathered over the last two decades suggests that beta amyloid (Abeta), the predominant proteinaceous component of senile plaques, plays an early and critical role in the etiology and pathogenesis of Alzheimer's disease (AD). Thus, it is reasonable to hypothesize that compounds capable of reducing the accumulation of Abeta may be of value therapeutically. Additionally, compounds that influence Abeta accumulation may be useful as tools to further dissect the cellular pathways that regulate Abeta production and accumulation. To screen for compounds that affect Abeta levels, we have established high throughput, cell-based assays capable of the sensitive and selective detection of Abeta40 in parallel with the more amyloidogenic form of the peptide, Abeta42. To validate the approach, we examined the effects of several compounds previously identified to influence Abeta accumulation. Analysis of peptide accumulation following treatment with these compounds showed results similar to those previously published. Currently, we are using this assay to screen drugs that have already received FDA approval for the treatment of other diseases and over-the-counter natural product extracts. If compounds such as these can be identified that lower Abeta in the brain, they may represent one of the fastest and most cost effective methods to therapy.

Authors

Haugabook, Sharie; Yager, D M; Eckman, E A; Golde, T E; Younkin, S G; Eckman, C B;

Keywords

  • Alzheimer Disease/ drug therapy
  • Alzheimer Disease/ metabolism
  • Alzheimer Disease/ physiopathology
  • Amyloid beta-Peptides/ analysis
  • Amyloid beta-Peptides/ drug effects
  • Amyloid beta-Peptides/ metabolism
  • Animals
  • Biological Assay/ instrumentation
  • Biological Assay/ methods
  • CHO Cells/ drug effects
  • CHO Cells/ metabolism
  • Cell Culture Techniques
  • Cell Survival/ drug effects
  • Cell Survival/ physiology
  • Cells, Cultured/ drug effects
  • Cells, Cultured/ metabolism
  • Cricetinae
  • Culture Media, Conditioned/ pharmacology
  • Drug Evaluation, Preclinical/ instrumentation
  • Drug Evaluation, Preclinical/ methods
  • Drug-Related Side Effects and Adverse Reactions/ metabolism
  • Enzyme-Linked Immunosorbent Assay/ methods
  • Humans
  • Neuroprotective Agents/ pharmacology
  • Peptide Fragments/ analysis
  • Peptide Fragments/ drug effects
  • Peptide Fragments/ metabolism
  • Reproducibility of Results
  • Toxicity Tests/ instrumentation
  • Toxicity Tests/ methods

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