A comprehensive study of the spatiotemporal pattern of β-amyloid precursor protein mRNA 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 Alzheimer's disease (AD). It has been suggested that NGF be used to treat AD patients. However, in vivo administration of NGF to the developing hamster brain was shown to induce the expression of the β-amyloid precursor protein (βAPP) gene. The association of alterations in βAPP gene expression with AD-like neuropathological changes and cognitive impairment in animals, and with AD-like neurodegeneration in Down syndrome patients suggests that NGF-mediated increases in βAPP expression could negate or attenuate NGF's neurotrophic activity in AD treatment trials. The present study was undertaken to explore further the influence of NGF on βAPP expression, and to determine which, if any, of the βAPP mRNAs is altered in response to NGF treatment. We first examined the spatiotemporal pattern of βAPP-695 and Kunitz protease inhibitor (KPI)-containing βAPP mRNA expression in the rat brain. Specific oligonucleotide probes were used to show that these mRNAs are present during embryonic development. In addition, we evaluated postnatal expression in nine brain regions and showed that βAPP mRNAs were readily detected in all regions at postnatal day 2. In human brain, the relative levels of βAPP-695 and βAPP-KPI mRNA and their protein are discordant, in that the level of βAPP-695 mRNA is slightly higher than that of βAPP-KPI, but βAPP-KPI protein predominates. In contrast, the several-fold excess of βAPP-695 mRNA relative to βAPP-KPI mRNA in the rat brain was also reflected at the protein level. Surprisingly, administration of exogenous NGF failed to affect rat βAPP mRNA levels either in vitro or during postnatal development in vivo.