Design of small molecules that target metal-A{beta} species and regulate metal-induced A{beta} aggregation and neurotoxicity.
The accumulation of metal ions and amyloid-β (Aβ) aggregates found in the brain of patients with Alzheimer's disease (AD) has been suggested to be involved in AD pathogenesis. To investigate metal-Aβ-associated pathways in AD, development of chemical tools to target metal-Aβ 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 Aβ species, as determined by spectroscopic methods including high-resolution NMR spectroscopy. Using the bifunctional compound L2-b, metal-induced Aβ 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 Aβ species with L2-b showed disassembly of Aβ aggregates. Therefore, our studies presented herein demonstrate the value of bifunctional compounds as chemical tools for investigating metal-Aβ-associated events and their mechanisms in the development and pathogenesis of AD and as potential therapeutics.
Department of Chemistry, Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA.
Jung-Suk
JS
Choi
Joseph J
JJ
Braymer
Ravi P R
RP
Nanga
Ayyalusamy
A
Ramamoorthy
Mi Hee
MH
Lim
D000544:Alzheimer Disease; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism*; D045744:Cell Line, Tumor; D003300:Copper / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D010655:Phenylenediamines / Q000737:chemistry / Q000494:pharmacology*; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*; D015032:Zinc / Q000737:chemistry / Q000494:pharmacology*
D016229:Amyloid beta-Peptides; C546967:N1,N1-dimethyl-N4-(pyridin-2-ylmethylene)benzene-1,4-diamine; D010655:Phenylenediamines; D011725:Pyridines; D003300:Copper; D015032:Zinc