A COMPREHENSIVE STUDY OF THE SPATIOTEMPORAL PATTERN OF BETA-AMYLOID PRECURSOR PROTEIN MESSENGER-RNA AND PROTEIN IN THE RAT-BRAIN - LACK OF MODULATION BY EXOGENOUSLY APPLIED NERVE GROWTH-FACTOR

Nerve growth factor (NGF) is a neurotrophic factor for basal forebrain cholinergic neurons? a population that degenerates and dies in Alzhei mer's disease (AD). It has been suggested that NGF be used to treat AD patients. However, in vivo administration of NGF to the developing ha mster brain was shown to induce the expression of the beta-amyloid pre cursor protein (beta APP) gene. The association of alterations in beta APP gene expression with AD-like neuropathological changes and cognit ive impairment in animals, and with AD-like neurodegeneration in Down syndrome patients suggests that NGF-mediated increases in beta APP exp ression could negate or attenuate NGF's neurotrophic activity in AD tr eatment trials. The present study was undertaken to explore further th e influence of NGF on beta APP expression, and to determine which, if any, of the beta APP mRNAs is altered in response to NGF treatment, We first examined the spatiotemporal pattern of beta APP-695 and Kunitz protease inhibitor (KPI)-containing beta APP mRNA expression in the ra t brain. Specific oligonucleotide probes were used to show that these mRNAs are present during embryonic development. In addition, we evalua ted postnatal expression in nine brain regions and showed that beta AP P mRNAs were readily detected in all regions at postnatal day 2. In hu man brain, the relative levels of beta APP-695 and beta APP-KPI mRNA a nd their protein are discordant, in that the level of beta APP-695 mRN A is slightly higher than that of beta APP-KPI, but beta APP-KPI prote in predominates. In contrast, the several-fold excess of beta APP-695 mRNA relative to beta APP-KPI mRNA in the rat brain was also reflected at the protein level. Surprisingly, administration of exogenous NGF f ailed to affect rat beta APP mRNA levels either in vitro or during pos tnatal development in vivo.