M1 muscarinic agonists target major hallmarks of Alzheimer's disease--the pivotal role of brain M1 receptors.

The 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 beta-amyloid (Abeta(40) and Abeta(42)) in rabbits, decreased brain Abeta levels in hypercholesterolemic rabbits and vascular Abeta(42) deposition from the cortex in cholinotoxin-treated rabbits. In triple transgenic AD mice, AF267B reduced cognitive deficits and decreased Abeta(42) and tau pathologies in the cortex and hippocampus (not amygdala), via M1 mAChR activation of protein kinase C and a disintegrin and metalloproteinase domain 17 (ADAM17 or TACE) and decreased beta-site amyloid precursor protein-cleaving enzyme 1 and glycogen synthase kinase 3beta, respectively. AF267B is the first reported low-molecular-weight therapy that targets the major AD hallmarks. 2008 S. Karger AG, Basel