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

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