Simultaneous changes in secretory amyloid precursor protein and β-amyloid peptide release from rat hippocampus by activation of muscarinic receptors

Abstract Amyloid deposits in Alzheimer's disease (AD) are composed of β-amyloid peptides (Aβ) that are derived from the larger amyloid precursor protein (APP). A number of studies with various transfected cell lines demonstrated that either APP secretion or Aβ production could be modulated by specific muscarinic receptor activation. In the present study, we investigated the simultaneous changes of neurotrophic secretory APP (APPs) and neurotoxic Aβ release from rat hippocampus by activation of muscarinic receptors. The treatment with carbachol (10 μM–1 mM) resulted in the increased APPs release and simultaneously reduced Aβ production from the hippocampus slices in a concentration-dependent manner. The carbachol-stimulated APPs release was blocked by the nonselective M antagonist atropine and the M 1 antagonist pirenzepine, but was not significantly affected by the M 2 antagonist methoctramine, demonstrating that APP processing was regulated mainly via M 1 receptor in the rat hippocampus. The effect of carbachol-stimulated APPs secretion was further verified in CHOm 1 cells stably expressing human muscarinic M 1 receptors. These data suggest that selective M 1 receptor agonists might execute a dual action of increasing APPs release and decreasing Aβ formation to modify the AD process.