Muscarinic agonists reduce tau phosphorylation in non-neuronal cells via GSK-3 beta inhibition and in neurons

Muscarinic agonists alter the metabolism of amyloid precursor protein, lead ing to an increase in alpha -secretase cleavage and a decreased production of amyloidogenic peptides; suggesting that these compounds might modify the Alzheimer's disease process. A second therapeutic target in AD is the accu mulation of stably phosphorylated tau into neurofibrillary tangles; an earl y event correlating with cognitive impairment. Glycogen synthase kinase-3 ( GSK-3 beta) phosphorylates tau and is inhibited via protein kinase C (PKC). As certain muscarinic receptors are linked to PKC, we examined the effect of a range of agonists on GSK-3 beta phosphorylation of tau. In neurons a n on-specific muscarinic agonist, carbachol, reduced tau phosphorylation. In non-neuronal cells expressing the m1 receptor a range of m1 agonists reduce d transiently-expressed tau phosphorylation and altered its microtubule-bin ding properties. These findings link the two pathological process of AD - A PP metabolism and tau phosphorylation - and suggest that muscarinic and oth er cholinergic compounds might have disease-modifying properties.