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

作者：Choi Jung Suk; Braymer Joseph J; Nanga Ravi P R; Ramamoorthy Ayyalusamy; Lim Mi Hee^*

来源：Proceedings of the National Academy of Sciences, 2010, 107(51): 21990-21995.

DOI：10.1073/pnas.1006091107

• amyloid-beta peptide
• copper
• zinc
• reactive oxygen species
• rational structure-based design

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.

• 出版日期2010-12-21