Summary.
Muscarinic agonists alter the metabolism of amyloid precursor protein, leading to an increase in α-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-3β) 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-3β phosphorylation of tau. In neurons a non-specific muscarinic agonist, carbachol, reduced tau phosphorylation. In non-neuronal cells expressing the m1 receptor a range of m1 agonists reduced transiently-expressed tau phosphorylation and altered its microtubule-binding 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.
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Received December 10, 1999; accepted March 14, 2000
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Forlenza, O., Spink, J., Dayanandan, R. et al. Muscarinic agonists reduce tau phosphorylation in non-neuronal cells via GSK-3β inhibition and in neurons. J Neural Transm 107, 1201–1212 (2000). https://doi.org/10.1007/s007020070034
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DOI: https://doi.org/10.1007/s007020070034