Design of small molecules that target metal-Aβ species and regulate metal-induced Aβ aggregation and neurotoxicity

The accumulation of metal ions and amyloid-beta (A beta) 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 beta-associated pathways in AD, development of chemical tools to target metal-A beta 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 beta species, as determined by spectroscopic methods including high-resolution NMR spectroscopy. Using the bifunctional compound L2-b, metal-induced A beta 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 beta species with L2-b showed disassembly of A beta aggregates. Therefore, our studies presented herein demonstrate the value of bifunctional compounds as chemical tools for investigating metal-A beta-associated events and their mechanisms in the development and pathogenesis of AD and as potential therapeutics.