title: Effects of the M1 agonist xanomeline on processing of human beta-amyloid precursor protein (FAD, Swedish mutant) transfected into Chinese hamster ovary-m1 cells.
abstract: Complementary DNA (cDNA) encoding human beta-amyloid precursor protein familial Alzheimer's disease (FAD) Swedish mutant (beta APPSM) 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 beta APPSM were isolated. The effects of m1-receptor activation by the selective m1 agonist xanomeline and the non-selective muscarinic agonist carbachol on processing of beta APPSM to release soluble APP (APPs) and beta-amyloid peptide (A beta) 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 A beta 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.
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, USA. nwd@lilly.com
authors.forename: N
authors.initials: N
authors.lastname: DeLapp
authors.forename: S
authors.initials: S
authors.lastname: Wu
authors.forename: R
authors.initials: R
authors.lastname: Belagaje
authors.forename: E
authors.initials: E
authors.lastname: Johnstone
authors.forename: S
authors.initials: S
authors.lastname: Little
authors.forename: H
authors.initials: H
authors.lastname: Shannon
authors.forename: F
authors.initials: F
authors.lastname: Bymaster
authors.forename: D
authors.initials: D
authors.lastname: Calligaro
authors.forename: C
authors.initials: C
authors.lastname: Mitch
authors.forename: C
authors.initials: C
authors.lastname: Whitesitt
authors.forename: J
authors.initials: J
authors.lastname: Ward
authors.forename: M
authors.initials: M
authors.lastname: Sheardown
authors.forename: A
authors.initials: A
authors.lastname: Fink-Jensen
authors.forename: L
authors.initials: L
authors.lastname: Jeppesen
authors.forename: C
authors.initials: C
authors.lastname: Thomsen
authors.forename: P
authors.initials: P
authors.lastname: Sauerberg
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D016466:CHO Cells; D002217:Carbachol / Q000494:pharmacology; D003001:Cloning, Molecular; D006224:Cricetinae; D006801:Humans; D018721:Muscarinic Agonists / Q000494:pharmacology*; D009154:Mutation; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000187:drug effects* / Q000235:genetics; D011725:Pyridines / Q000494:pharmacology*; D043643:Receptor, Muscarinic M1; D011976:Receptors, Muscarinic / Q000502:physiology*; D013548:Sweden; D013830:Thiadiazoles / Q000494:pharmacology*; D014162:Transfection
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D018721:Muscarinic Agonists; D010446:Peptide Fragments; D011725:Pyridines; D043643:Receptor, Muscarinic M1; D011976:Receptors, Muscarinic; D013830:Thiadiazoles; D002217:Carbachol; C075257:xanomeline