GLUTAMATE-STIMULATED SECRETION OF AMYLOID PRECURSOR PROTEIN FROM CORTICAL RAT-BRAIN SLICES

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.