High throughput screens for the identification of compounds that alter the accumulation of the Alzheimer's amyloid β peptide (Aβ)

Abstract

Evidence gathered over the last two decades suggests that β amyloid (Aβ), 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 Aβ may be of value therapeutically. Additionally, compounds that influence Aβ accumulation may be useful as tools to further dissect the cellular pathways that regulate Aβ production and accumulation. To screen for compounds that affect Aβ levels, we have established high throughput, cell-based assays capable of the sensitive and selective detection of Aβ40 in parallel with the more amyloidogenic form of the peptide, Aβ42. To validate the approach, we examined the effects of several compounds previously identified to influence Aβ 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 Aβ in the brain, they may represent one of the fastest and most cost effective methods to therapy.