Small molecules that protect against beta-amyloid-induced cytotoxicity by inhibiting aggregation of beta-amyloid

Abstract

Aggregated beta-amyloid (A beta) plays crucial roles in Alzheimer's disease (AD) pathogenesis, therefore blockade of Ab aggregation is considered as a potential therapeutic target. We designed and synthesized small molecules to reduce A beta-induced cytotoxicity by inhibiting A beta aggregation. The small molecules were screened via ThT, MTT, and cell-based cytotoxicity assay (A beta burden assay). Selected compounds 1c, 1d, 1e, and 1f were then investigated by evaluating their effects on cognitive impairment of acute AD mice model. Learning and memory dysfunction by injection of A beta(1-42) was recovered by administration of these molecules. Especially, 1d showed the best recovery activity in Y-maze task, object recognition task, and passive avoidance task with dose dependent manner. These results suggest that 1d has high potential as a therapeutic agent for AD. (C) 2012 Elsevier Ltd. All rights reserved.