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.