REGULATED SECRETION OF BETA-AMYLOID PRECURSOR PROTEIN IN RAT-BRAIN

The beta-amyloid precursor protein (APP) is a ubiquitous, highly conse rved secretory glycoprotein that is expressed at high levels in mammal ian brain by neurons, astrocytes, and activated microglia. Secreted AP P (APP(s)) is generated by the cleavage of APP within the beta-amyloid (AP) portion of its ectodomain. The formation and secretion of APP(s) can be increased by activation of particular neurotransmitter recepto rs and subsequent protein phosphorylation. We found that tissue slices from rat cortex, hippocampus, striatum,and cerebellum secrete APP(s) in vitro. APP(s) secretion was enhanced by electrical stimulation, but was not associated with a general increase in the release of total pr otein, lactate dehydrogenase (LDH) activity, or neuronal cell adhesion molecules. The pharmacological profile of stimulation-induced APP(s) secretion suggests complex interactions between muscarinic receptor su btypes in the tissue slices: in the unstimulated state, activation of Muscarinic Mi receptors increased APP(s) release while nonspecific act ivation of multiple muscarinic receptors had little effect on APP(s) r elease; in electrically stimulated slices, nonspecific inhibition of m uscarinic receptors blunted the increase in APP secretion. The nonspec ific muscarinic agonist carbachol increased APP(s) secretion only in t he presence of an M2 receptor antagonist, suggesting that activation o f M2 receptors suppresses APP(s) formation. These data indicate that s ecretory APP processing in brain includes depolarization-enhanced clea vage of the cell-associated holoprotein within its ectodomain, and tha t the net effect of depolarization involves several subtypes of acetyl choline receptors.