EFFECTS OF THE M1 AGONIST XANOMELINE ON PROCESSING OF HUMAN BETA-AMYLOID PRECURSOR PROTEIN (FAD, SWEDISH MUTANT) TRANSFECTED INTO CHINESE-HAMSTER OVARY-M1 CELLS

Complimentary DNA (cDNA) encoding human beta-amyloid precursor protein familial Alzheimer's disease (FAD) Swedish mutant (beta APP(SM)) form was cloned into a mammalian expression vector (PK255) containing the CMV promoter. The vector was transfected into Chinese hamster ovary ce lls containing human muscarinic m1 receptors (CHO-m1), and clonal cell s stably expressing beta APP(SM) were isolated, The effects of m1-rece ptor activation by the selective m1 agonist xanomeline and the non-sel ective muscarinic agonist carbachol on processing of beta APP(SM) to r elease soluble APP (APPs) and beta-amyloid peptide (A beta) were compa red. Xanomeline stimulated APP release with a potency 1000-fold greate r than that observed for carbachol. Concentrations of carbachol and xa nomeline producing maximal effects on APPs release reduced the secreti on of A beta by 28 and 46%, respectively. These results extend previou s studies with xanomeline and suggest that cholinergic replacement the rapy for Alzheimer's disease may reduce amyloid deposition. (C) 1998 A cademic Press.