6beta-acetoxy nortropane regulated processing of amyloid precursor protein in CHOm1 cells and rat brain.
The effects of the muscarinic receptor agonist 6beta-acetoxy nortropane on amyloid precursor protein (APP) processing were studied in both transfected Chinese hamster ovary cells stably expressing muscarinic M(1) receptors (denoted as CHOm(1) cell line) and in cerebral cortical and hippocampal slices. Exposure of CHOm(1) cells to 6beta-acetoxy nortropane for 1 h significantly increased the secretion of secretory amyloid precursor protein (derived from alpha-secretase cleavage) in a concentration-dependent manner. In the same system, 6beta-acetoxy nortropane reduced the beta-amyloid peptide production. Similar results were obtained in hippocampal and cerebral cortical slices, with 6beta-acetoxy nortropane administration resulting in an increase in secretory amyloid precursor protein and a decrease in beta-amyloid peptide release. The increase of secretory amyloid precursor protein secretion was abolished by preincubation with selective muscarinic M(1) receptor antagonist pirenzepine, but not by preincubation with selective muscarinic M(2) receptor antagonist methoctramine, suggesting that 6beta-acetoxy nortropane promotes secretory amyloid precursor protein release in the brain via muscarinic M(1) receptor activation. These results suggest that 6beta-acetoxy nortropane could exert a beneficial effect on the progress of Alzheimer's disease by promoting amyloid precursor protein processing through alpha-secretase.
Department of Pharmacology, Drug Research Institute, Shanghai Second Medical University, Shanghai 200025, China.
Yu
Y
Qiu
Hong-zhuan
HZ
Chen
Xing-jun
XJ
Wu
Zheng-jun
ZJ
Jin
D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D001285:Atropine / Q000494:pharmacology; D016466:CHO Cells; D002217:Carbachol / Q000494:pharmacology; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism; D006224:Cricetinae; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D015151:Immunoblotting; D066298:In Vitro Techniques; D008297:Male; D018721:Muscarinic Agonists / Q000494:pharmacology*; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009662:Nortropanes / Q000494:pharmacology*; D010890:Pirenzepine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043643:Receptor, Muscarinic M1; D011976:Receptors, Muscarinic / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D018721:Muscarinic Agonists; D018727:Muscarinic Antagonists; D009662:Nortropanes; D043643:Receptor, Muscarinic M1; D011976:Receptors, Muscarinic; C071344:6-acetoxynortropane; D010890:Pirenzepine; D001285:Atropine; D002217:Carbachol