Alzheimer's disease (AD) is a degenerative disorder of the central nervous system. Some cases show a pattern of autosomal dominant transmission and are referred to as familial AD (FAD). To date three genes involved in FAD have been identified. One of these genes, presenilin-1 (PS-1), is the most commonly recognized cause of early onset FAD. The functions of the PS-1 protein are incompletely understood. Null mutations in the PS-1 gene in mice strongly suggest that PS-1 plays a critical role in neurogenesis. Recently we found that over expression of wild type but not an FAD mutant PS-1 promotes neurogenesis in the hippocampus of adult mice. Here we propose to extend these findings using both PS-1 transgenic and PS-1 null mutant mice to better define the role of PS-1 in neural injury and repair as well as CNS development and to determine if the PS-1 FAD mutant P11 7L is defective in certain functions. Specifically we will determine whether neuronal over expression of PS-1 or a PS-1 FAD mutant in transgenic mice effects reactive synaptogerlesis, neurite outgrowth and reactive neurogenesis in the hippocampus after entorhinal cortex lesions. We will also determine whether over expression of PS-1 or a PS-1 FAD mutant in transgenic mice influences performance on several tests of learning and memory after entorhinal cortex lesions. Additionally we will use a nestin promoter to over express PS-1 in neural progenitor cells. We will assess the effect of over express sing PS-1 in neural progenitors on neurogenesis and gliogenesis in embryonic brain and also assess how neurogenesis and gliogenesis is affected in PS-1 null mutant embryos. We will also determine whether a PS-1 transgene controlled by a nestin promoter can rescue the embryonic lethality of a PS-1 null mutation. Collectively these studies will provide a better understanding of the normal functions of PS-1 and determine whether an FAD mutant is defective in certain functions. Results from these studies could have implications for understanding how FAD mutants cause AD.
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