Simultaneous changes in secretory amyloid precursor protein and beta-amyloid peptide release from rat hippocampus by activation of muscarinic receptors.
Amyloid deposits in Alzheimer's disease (AD) are composed of beta-amyloid peptides (Abeta) 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 Abeta 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 Abeta release from rat hippocampus by activation of muscarinic receptors. The treatment with carbachol (10 microM-1 mM) resulted in the increased APPs release and simultaneously reduced Abeta 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 Abeta formation to modify the AD process.
Qiu
Yu
Y
Department of Pharmacology, Shanghai Second Medical University, Shanghai 200025, China.
Wu
Xing-Jun
XJ
Chen
Hong-Zhuan
HZ
D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D004305:Dose-Response Relationship, Drug; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D066298:In Vitro Techniques; D018721:Muscarinic Agonists / Q000494:pharmacology; D010446:Peptide Fragments / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011976:Receptors, Muscarinic / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D018721:Muscarinic Agonists; D010446:Peptide Fragments; D011976:Receptors, Muscarinic