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

Research output: Contribution to journalArticle

O V Forlenza, J M Spink, R Dayanandan, B H Anderton, O F Olesen, S Lovestone

Original languageEnglish
Pages (from-to)1201 - 1212
Number of pages12
JournalJournal of Neural Transmission
Volume107
Issue number10
DOIs
Publication statusPublished - 2000

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  • King's College London

Abstract

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-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 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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