The Amyloid Precursor Protein (APP) is a highly conserved multifunctional protein, showing expression in a broad range of tissues during the mammalian life cycle. The normal functional role(s) of the protein is poorly understood, but evidence from a variety of sources suggest an involvement in cell contact, growth, and repair processes as well as hemostasis. The abnormal expression of the protein and its multiple modified forms has been implicated in Alzheimer's Disease (AD). Heretofore, emphasis has been directed primarily to an understanding of post-transcriptional modification of the APP mRNA and protein products, but a complete understanding of APP and its role in pathogenesis requires a comparable understanding of the transcriptional control of APP gene expression, particularly within a developmental context. In the present grant proposal, we introduce a new methodology designed to rapidly produce detailed information on the control of APP gene regulation in the context of the intact organism undergoing normal ontogeny. This will be accomplished by first establishing the normal patterns of APP expression by means of in situ immunomicroscopy. Secondly, we will use APP reporter constructs in transgenic mice to determine the regulatory role of subregions of the APP gene in comparison with the normal patterns of APP gene expression. Thirdly, we will employ molecular methods to detect specific response elements, and then confirm this analysis by means of the transgenic approach. We have already established the efficacy of this approach with other genes, and we have begun to apply this analysis to the APP gene specifically in the context of the development of the CNS and the cytodifferentiation of the megakaryocyte lineage of the blood elements.
| Salbaum, J M; Ruddle, F H (1994) Embryonic expression pattern of amyloid protein precursor suggests a role in differentiation of specific subsets of neurons. J Exp Zool 269:116-27 |
