Lu 25-109, a combined m1 agonist and m2 antagonist, modulates regulated processing of the amyloid precursor protein of Alzheimer's disease.
To examine the effects of the combined muscarinic ml-agonist/m2-antagonist Lu 25-109 on regulated processing of the amyloid protein precursor (APP), we used both transfected cells expressing human muscarinic m1 or m2 acetylcholine receptors, and fresh rat hippocampal slices. Lu 25-109 readily stimulated APPs secretion from HEK 293 cells overexpressing m1, but not m2, receptors, as well as from the hippocampal brain slices. Time-course analyses revealed a rapid (5-35 minutes), and a delayed (55-75 minutes) secretory response to Lu 25-109 with distinct concentration profiles suggesting two distinct cell biological mechanisms. Both responses appeared to reflect post-translational mechanisms because levels of APP message were unchanged after 60 minutes of stimulation with Lu 25-109. In comparison to carbachol, Lu 25-109 had a significantly lower intrinsic activity at muscarinic m1 receptors, compatible with a pharmacological profile as a partial agonist at recombinantly expressed m1 receptors. In as much as stimulation of APPs secretion is associated with reduced formation of A beta peptides, Lu 25-109 may be useful to reduce A beta generation, and thus, slow amyloid plaque formation. Moreover, Lu 25-109 may be useful in promoting the known neurotrophic and neuroprotective biological functions of secreted APPs.
Müller
D
D
Center for Molecular Neurobiology and Alzheimer's Disease Research Group, University of Hamburg, Federal Republic of Germany.
Wiegmann
H
H
Langer
U
U
Moltzen-Lenz
S
S
Nitsch
R M
RM
D000544:Alzheimer Disease / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D018721:Muscarinic Agonists / Q000494:pharmacology*; D018727:Muscarinic Antagonists / Q000494:pharmacology*; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D011917:Rats, Inbred Lew; D013777:Tetrazoles / Q000494:pharmacology*; D014162:Transfection
D016564:Amyloid beta-Protein Precursor; C108369:LU 25-109-T; D018721:Muscarinic Agonists; D018727:Muscarinic Antagonists; D011725:Pyridines; D013777:Tetrazoles