L. Kirazov et al., GLUTAMATE-STIMULATED SECRETION OF AMYLOID PRECURSOR PROTEIN FROM CORTICAL RAT-BRAIN SLICES, Neurochemistry international, 30(6), 1997, pp. 557-563
The aim of this study was to determine whether L-glutamate, a major ex
citatory transmitter in the cerebral cortex, modulates the proteolytic
cleavage of the amyloid precursor protein (APP) in the brain through
specific receptor activation. Native rat brain cerebral cortical slice
s were stimulated either with L-glutamate or various glutamate recepto
r agonists, and the soluble APP derivatives released into the incubati
on medium were assayed by Western blot analysis. Immunoprecipitation w
ith specific antibodies revealed that in the medium only secretory for
ms of APP lacking intact C terminus were present, whereas in the brain
slices both C- and N-terminal intact APP products were detectable. L-
glutamate induced the release of secretory APP from cortical slices in
a concentration-dependent but biphasic manner, with the highest relea
se at 50 mu M L-glutamate and smaller effects at higher glutamate conc
entrations. To determine whether the effect of L-glutamate is mediated
through distinct glutamate receptor subtypes, brain slices were incub
ated in the presence of various specific glutamate receptor agonists.
Activation of the pha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic a
cid (AMPA) receptor with 50 nM (RS)-bromohomoibotenic acid resulted in
a reduced release of secretory APP by 17% +/- 3 (P < 0.01, one tailed
Student's t-test) compared to the incubation without any drug. Stimul
ation of the metabotropic glutamate receptor with 50 nM (2S,3S,4S)-alp
ha-(carboxycyclopropyl)-glycine (L-CCG-I) led to an enhanced release o
f secretory APP by 39% +/- 3 (P < 0.001), whereas activation of the N-
methyl-D-aspartate (NMDA) receptor with 50 nM (1R,3R)-1-aminocyclopent
ane-1,3-dicarboxylic acid ((1R,3R)-ACPD) did not significantly change
the secretion of APP compared to the incubation without any drug. The
data suggest that: (i) cortical glutamatergic neurotransmission is inv
olved in APP metabolism; and (ii) the stimulation of APP cleavage in c
erebral cortical brain slices is mainly mediated by the metabotropic b
ut not the NMDA glutamate receptor subtype, whereas the AMPA receptor
subtype seems to inhibit the secretory path of APP processing. (C) 199
7 Elsevier Science Ltd.