6β-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-2 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. (C) 2003 Elsevier Science B.V All rights reserved.