Effects of the M1 agonist xanomeline on processing of human beta-amyloid precursor protein (FAD, Swedish mutant) transfected into Chinese hamster ovary-m1 cells.
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.
DeLapp
N
N
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, USA. nwd@lilly.com
Wu
S
S
Belagaje
R
R
Johnstone
E
E
Little
S
S
Shannon
H
H
Bymaster
F
F
Calligaro
D
D
Mitch
C
C
Whitesitt
C
C
Ward
J
J
Sheardown
M
M
Fink-Jensen
A
A
Jeppesen
L
L
Thomsen
C
C
Sauerberg
P
P
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
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