lithium-chloride and xanomeline

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.

Topics: 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; tau Proteins; Tetrazoles; Thiadiazoles