Inhibiting Aβ toxicity in Alzheimer's disease by a pyridine amine derivative

Abstract Alzheimer's disease (AD) is a neurodegenerative disorder with no radical therapy. Aggregation of amyloid β -peptide (A β ) induced by various factors is associated with pathogenesis of AD. A pyridine amine derivative, 3-bis(pyridin-2-ylmethyl)aminomethyl-5-hydroxybenzyltriphenylphosphonium bromide (PAT), is synthesized. The inhibition of self- and metal-induced A β aggregation by PAT is confirmed by thioflavine T fluorescence, circular dichroism spectroscopy, and TEM. Western blot, RT-PCR and fluorescence imaging indicate that PAT can alleviate the A β -induced paralysis, reduce the production of ROS, and protect the mitochondrial function in transgenic C. elegans . Genetic analyses indicate that heat shock protein is involved in the alleviation of A β toxicity. PAT also inhibits the activity of acetylcholinesterase in C. elegans . Morris water maze test shows that the memory and cognitive ability of APP/PS1 AD model mice are significantly improved by PAT. Both in vitro and in vivo studies demonstrate that PAT is effective in counteracting A β toxicity and ameliorating cognitive functions in AD mice, and therefore a potential lead compound of anti-AD drugs.