Muscarinic M1 receptor agonists increase the secretion of the amyloid precursor protein ectodomain.
Amyloid deposits in Alzheimer's disease are composed of amyloid beta-peptides (A beta) that are derived from the larger amyloid precursor protein (APP). Proteolytic APP processing is activity-dependent, and it can be regulated by muscarinic acetylcholine receptors. In particular, muscarinic m1 receptor subtypes increase cleavage within the A beta domain, followed by the release of the soluble APP ectodomain (APPs). In this study, we show that the m1-selective agonist talsaclidine concentration-dependently increased APPs release from both transfected human astrocytoma cell lines and rat brain slices. This increase was blocked by atropine. In contrast, the M2 antagonist BIBN 99 failed to increase APPs release, and decreased it at higher concentrations. These results show that talsaclidine can effectively modulate alpha-secretase processing of APP in human cell lines and in brain tissue. The data suggest that talsaclidine may be a useful candidate drug to modulate APP processing in Alzheimer's disease.
Müller
D M
DM
Center for Molecular Neurobiology, University of Hamburg, Germany.
Mendla
K
K
Farber
S A
SA
Nitsch
R M
RM
D053829:Amyloid Precursor Protein Secretases; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D003984:Dibenzazepines / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D010450:Endopeptidases / Q000502:physiology; D006801:Humans; D008297:Male; D018721:Muscarinic Agonists / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D011917:Rats, Inbred Lew; D043643:Receptor, Muscarinic M1; D011976:Receptors, Muscarinic / Q000187:drug effects*; D014407:Tumor Cells, Cultured
D016564:Amyloid beta-Protein Precursor; D003984:Dibenzazepines; D018721:Muscarinic Agonists; D011725:Pyridines; D043643:Receptor, Muscarinic M1; D011976:Receptors, Muscarinic; C079888:BIBN 99; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human