MUSCARINIC M1 RECEPTOR AGONISTS INCREASE THE SECRETION OF THE AMYLOIDPRECURSOR PROTEIN ECTODOMAIN

Amyloid deposits in Alzheimer's disease are composed of amyloid beta-p eptides (A beta) that are derived from the larger amyloid precursor pr otein (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 d omain, followed by the release of the soluble APP ectodomain (APPs). I n this study, we show that the m1-selective agonist talsaclidine conce ntration-dependently increased APPs release from both transfected huma n astrocytoma cell lines and rat brain slices. This increase was block ed by atropine. In contrast, the M2 antagonist BIBN 99 failed to incre ase APPs release, and decreased it at higher concentrations. These res ults show that talsaclidine can effectively modulate alpha-secretase p rocessing of APP in human cell lines and in brain tissue. The data sug gest that talsaclidine may be a useful candidate drug to modulate APP processing in Alzheimer's disease.