M1 muscarinic Agonists target major hallmarks of Alzheimer's disease the pivotal role of brain M1 receptors

M1 muscarinic receptor (M1 mAChR) is a therapeutic target in Alzheimer's disease (AD) and the M1-selective muscarinic agonists AF102B, AF150(S) and AF267B are cognitive enhancers and potential disease modifiers. Notably, AF267B decreased cerebrospinal fluid P-amyloid (A beta(40) and A beta(42)) in rabbits, decreased brain A beta levels in hypercholesterolemic rabbits and vascular A beta(42) deposition from the cortex in cholinotoxin-treated rabbits. In triple transgenic AD mice, AF267B reduced cognitive deficits and decreased A beta(42) and tau pathologies in the cortex and hippocampus (not amygdala), via M-1 mAChR activation of protein kinase C and a disintegrin and metalloproteinase domain 17 (ADAM17 or TACE) and decreased P-site amyloid precursor protein-cleaving enzyme I and glycogen synthase kinase 3 beta, respectively. AF267B is the first reported low-molecular-weight therapy that targets the major AD hallmarks. Copyright (c) 2008 S. Karger AG, Basel.