ACTIVATION OF M(1) MUSCARINIC ACETYLCHOLINE-RECEPTOR REGULATES TAU-PHOSPHORYLATION IN TRANSFECTED PC12 CELLS

Hyperphosphorylated tau proteins are the principal fibrous component o f the neurofibrillary tangle pathology in Alzheimer's disease. The pos sibility that tau phosphorylation is controlled by cell surface neurot ransmitter receptors was examined in PC12 cells transfected with the g ene for the rat m(1) muscarinic acetylcholine receptor. Stimulation of m(1) receptor in these cells with two acetylcholine agonists, carbach ol and AF102B, decreased tau phosphorylation, as indicated by specific tau monoclonal antibodies that recognize phosphorylation-dependent ep itopes and by alkaline phosphatase treatment. The muscarinic effect wa s both time and dose dependent. in addition, a synergistic effect on t au phosphorylation was found between treatments with muscarinic agonis ts and nerve growth factor. These studies provide the first evidence f or a link between the cholinergic signal transduction system and the n euronal cytoskeleton that can be mediated by regulated phosphorylation of tau microtubule-associated protein.