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Muscarinic agonists alter the metabolism of amyloid precursor protein, leading 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 accumulation of stably phosphorylated tau into neurofibrillary tangles; an early event correlating with cognitive impairment. Glycogen synthase kinase-3 (GSK-3beta) 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-3beta phosphorylation of tau. In neurons a nonspecific muscarinic agonist, carbachol, reduced tau phosphorylation. In nonneuronal cells expressing the ml receptor a range of ml agonists reduced transiently-expressed tau phosphorylation and altered its microtubulebinding properties. These findings link the two pathological process of AD-APP metabolism and tau phosphorylation - and suggest that muscarinic and other cholinergic compounds might have disease-modifying properties.

Original publication




Journal article


J Neural Transm (Vienna)

Publication Date





1201 - 1212


Acetylcholine, Alzheimer Disease, Amyloid beta-Protein Precursor, Animals, Binding Sites, Calcium-Calmodulin-Dependent Protein Kinases, Carbachol, Cells, Cultured, Fetus, Glycogen Synthase Kinase 3, Glycogen Synthase Kinases, Lithium Chloride, Microtubules, Muscarinic Agonists, Neurons, Phosphorylation, Pyridines, Rats, Rats, Sprague-Dawley, Receptors, Muscarinic, Tetrazoles, Thiadiazoles, tau Proteins