Excitatory Amino Acid‐induced Changes in Amygdaloid and Hippocampal APP mRNA Expression: Effect of Selective Antagonists

D. M. Pache*, R. Hutchings, R. D.E. Sewell, G. A. Foster, P. S.J. Spencer

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

1 Citation (Scopus)

Abstract

Changes in the expression of specific isoforms of amyloid precursor protein (APP) have been implicated in the pathogenesis of Alzheimer's disease. We have exploited the technique of in‐situ hybridization to determine whether the expression of two different isoforms of APP mRNA (APP695 and APP770) can be differentially affected by the activity of specific excitatory amino acid receptors. The hybridization signal for APP695 mRNA was reduced in animals treated intrahippocampally with vehicle followed by quisqualic acid around the area of injection, but increased in the amygdaloid region. The signal for the mRNA transcript of APP770 was detectably increased in the hippocampus but more so in the amygdala. Pretreatment with 2,3‐dihydro‐6‐nitro‐7‐sulphamoyl‐benzo(F)quinoxaline (NBQX, an α‐amino3‐hydroxy‐5‐methylsiloxasole‐4‐propionic acid receptor antagonist) prevented the quisqualic acid‐induced loss of APP695 mRNA signal but did not inhibit the increased APP770 mRNA transcript signal. Furthermore, it did not prevent the rise in the hybridization signals of either isoform in the amygdala. Conversely, D‐2‐amino‐5‐phosphonovaleric acid (AP5; a competitive antagonist at N‐methyl‐D‐aspartate (NMDA) receptors) inhibited the quisqualic acid‐induced increase of both mRNA transcripts in the amygdala but had little or no effect at the local injection site. Ibotenic acid did not modify amygdaloid expression of either APP mRNA transcript. However, the change in expression of both APP695 mRNA and APP770 mRNA induced by the intrahippocampal administration of ibotenic acid was inhibited by the competitive NMDA receptor antagonist AP5, but not by 5,7‐dichlorokynurenic acid (a glycine site antagonist of the NMDA receptor), nor by NBQX. These results suggest that the expression of the Kunitz family of serine protease inhibitors (KPI)‐containing and non‐KPI‐containing isoforms of APP can be differentially influenced by excitatory amino acid receptor activation and that this effect is sensitive to specific competitive, rather than non‐competitive, excitatory amino acid receptor antagonism. Moreover, they also suggest that a neurotransmitter‐targeted approach to the manipulation of APP expression and, by inference, management of Alzheimer's disease, may be possible. 1995 Royal Pharmaceutical Society of Great Britain

Original languageEnglish
Pages (from-to)209-214
Number of pages6
JournalJournal of Pharmacy and Pharmacology
Volume1
Issue number5-6
DOIs
Publication statusPublished - 1995
Externally publishedYes

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