The goal of this Project of our Alzheimer's Disease Research Center is to define the consequences of overexpression or ablation of the amyloid precursor protein (APP) on the phenotype of transgenic animals. A classical feature of cases of Alzheimer's disease (AD) and older individuals with Down's syndrome (DS) is the deposition of the beta- amyloid protein (A-beta) in the cerebral parenchyma and around blood vessels. A-beta is derived from APP and coded for by a gene on human chromosome 21; APP transcripts code for several isoforms, including APP- 695 (enriched in the brain, localized in neurons, and transported rapidly to nerve terminals) and APP-751, a protease inhibitor domain containing isoforms (present in brain and systemic organs). Factors that predispose to amyloidogenesis include: the overexpression of APP; mutations in the APP gene, as documented in some families as early-onset AD; altered APP processing, as occurs in vitro with some APP mutations; and a less well understood contribution by alterations in genes located on chromosomes 14 and 19. Unfortunately, to date, animal models of AD and DS do not reproduce the human phenotype. First, to test the hypothesis that overexpression of APP can lead to A-beta deposits, we have introduced a human APP genomic clone into the mouse germline using yeast artificial chromosome (YAC) cloning vectors and embryonic stem (ES) cells. Animals express transgene products in brain and systemic tissues at levels similar to that of the endogenous APP gene. Animals will be examined over time to determine if they develop amyloid deposits and other AD/DS- related cellular pathology; if so, we will use these animals as models to study the mechanisms of diseases. Second, because APP has been suggested to be a growth factor, a mediator of cell adhesion, a signal transduction protein, a regulator in coagulation cascades, and a participant in neural development, our second aim is to try to define some of the normal functions of APP, particularly in the brain. To investigate the functional roles of APP in mammalian development, the expression of the mouse APP will be ablated gene through gene targeting in ES cells, a strategy that has proved successful for the functional analysis of other genes involved in the development/function of the central nervous system. In concert, these two lines of investigation will provide new information concerning the role of APP overexpression in the development of amyloid deposits and will clarify the roles of APP in mouse development.
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