Amyloid precursor protein secretion via muscarinic receptors: reduced desensitization using the M1-selective agonist AF102B

Secretion of amyloid precursor protein (APP) by cultured cells is coupled to several receptors, including m1 muscarinic (m1AChR), and is associated with decreased production of βA4 amyloid. Secreted and cell-associated APP levels were measured in m1AChR-transfected PC12 cells stimulated with the non-selective agonist carbachol or the Mi-selective agonist, AF102B. Secreted APP levels following stimulation with AF102B (5-60 min) were about half compared with carbachol. Yet, following 24 h stimulation with carbachol or AF102B, cell-associated APP levels were similarly decreased. This may be associated with a smaller reduction in APP secretion following 24 h stimulation with AF102B as compared with carbachol. AF102B may therefore have an advantage over non-selective muscarinic ligands for sustained decrease of cell-associated APP.