Effects of the M1 Agonist Xanomeline on Processing of Human β-Amyloid Precursor Protein (FAD, Swedish Mutant) Transfected into Chinese Hamster Ovary-m1 Cells

Abstract Complimentary DNA (cDNA) encoding human β-amyloid precursor protein familial Alzheimer's disease (FAD) Swedish mutant (βAPP SM ) form was cloned into a mammalian expression vector (PK255) containing the CMV promoter. The vector was transfected into Chinese hamster ovary cells containing human muscarinic m1 receptors (CHO-m1), and clonal cells stably expressing βAPP SM were isolated. The effects of m1-receptor activation by the selective m1 agonist xanomeline and the non-selective muscarinic agonist carbachol on processing of βAPP SM to release soluble APP (APPs) and β-amyloid peptide (Aβ) were compared. Xanomeline stimulated APP release with a potency 1000-fold greater than that observed for carbachol. Concentrations of carbachol and xanomeline producing maximal effects on APPs release reduced the secretion of Aβ by 28 and 46%, respectively. These results extend previous studies with xanomeline and suggest that cholinergic replacement therapy for Alzheimer's disease may reduce amyloid deposition.