Effects of the M1 agonist xanomeline on processing of human beta-amyloid precursor protein (FAD, Swedish mutant) transfected into Chinese hamster ovary-m1 cells

Biochem Biophys Res Commun. 1998 Mar 6;244(1):156-60. doi: 10.1006/bbrc.1998.8235.

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.

MeSH terms

  • Alzheimer Disease / genetics
  • Amyloid beta-Peptides / genetics
  • Amyloid beta-Peptides / metabolism
  • Amyloid beta-Protein Precursor / genetics*
  • Amyloid beta-Protein Precursor / metabolism*
  • Animals
  • Blotting, Western
  • CHO Cells
  • Carbachol / pharmacology
  • Cloning, Molecular
  • Cricetinae
  • Humans
  • Muscarinic Agonists / pharmacology*
  • Mutation*
  • Peptide Fragments / genetics
  • Peptide Fragments / metabolism
  • Protein Processing, Post-Translational / drug effects*
  • Protein Processing, Post-Translational / genetics
  • Pyridines / pharmacology*
  • Receptor, Muscarinic M1
  • Receptors, Muscarinic / physiology*
  • Sweden
  • Thiadiazoles / pharmacology*
  • Transfection*

Substances

  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Muscarinic Agonists
  • Peptide Fragments
  • Pyridines
  • Receptor, Muscarinic M1
  • Receptors, Muscarinic
  • Thiadiazoles
  • Carbachol
  • xanomeline