Design of small molecules that target metal-A{beta} species and regulate metal-induced A{beta} aggregation and neurotoxicity.

ABSTRACT: The accumulation of metal ions and amyloid-? (A?) aggregates found in the brain of patients with Alzheimer's disease (AD) has been suggested to be involved in AD pathogenesis. To investigate metal-A?-associated pathways in AD, development of chemical tools to target metal-A? species is desired. Only a few efforts, however, have been reported. Here, we report bifunctional small molecules, N-(pyridin-2-ylmethyl)aniline (L2-a) and N(1),N(1)-dimethyl-N(4)-(pyridin-2-ylmethyl)benzene-1,4-diamine (L2-b) that can interact with both metal ions and A? species, as determined by spectroscopic methods including high-resolution NMR spectroscopy. Using the bifunctional compound L2-b, metal-induced A? aggregation and neurotoxicity were modulated in vitro as well as in human neuroblastoma cells. Furthermore, treatment of human AD brain tissue homogenates containing metal ions and A? species with L2-b showed disassembly of A? aggregates. Therefore, our studies presented herein demonstrate the value of bifunctional compounds as chemical tools for investigating metal-A?-associated events and their mechanisms in the development and pathogenesis of AD and as potential therapeutics.

SUBMITTER: Choi JS 

PROVIDER: S-EPMC3009803 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature