Abstract
Amyloid deposits in Alzheimer's disease are composed of amyloid beta-peptides (A beta) that are derived from the larger amyloid precursor protein (APP). Proteolytic APP processing is activity-dependent, and it can be regulated by muscarinic acetylcholine receptors. In particular, muscarinic m1 receptor subtypes increase cleavage within the A beta domain, followed by the release of the soluble APP ectodomain (APPs). In this study, we show that the m1-selective agonist talsaclidine concentration-dependently increased APPs release from both transfected human astrocytoma cell lines and rat brain slices. This increase was blocked by atropine. In contrast, the M2 antagonist BIBN 99 failed to increase APPs release, and decreased it at higher concentrations. These results show that talsaclidine can effectively modulate alpha-secretase processing of APP in human cell lines and in brain tissue. The data suggest that talsaclidine may be a useful candidate drug to modulate APP processing in Alzheimer's disease.
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