APP plays central roles in Alzheimer?s disease (AD) pathogenesis. It is cleaved to produce AB that is a major component of amyloid plaque observed in AD. The cleavage also produces intracellular region of APP (AICD) that, together with its interacting proteins such as Fe65, goes to nucleus where it regulates gene expression. Our recent study identified that Fe65 interacts with Teashirt (Tsh) protein, and together silence gene expression of sets of genes. We also found that expression of Fe65 and Tsh3 is decreased even in early stage of AD. Furthermore, genetic association studies identified protective alleles for TSHZ3 that encodes a gene for Tsh3 that are associated with higher expression of Tsh3. Finally, one of genes regulated by Fe65-Tsh3 is CASP4, a gene for caspase-4, a primate specific inflammatory caspase, which also show upregulation with AD progression. These results lead to our hypothesis that APP-Fe65-Tsh pathway suppresses expression of genes, such as caspase-4 and by doing so, protects against AD progression, and that disinhibition of this pathway contributes to AD pathogenesis. In the current proposal, we will test our hypothesis by using animal models. Since CASP4 is primate specific, we will introduce human caspase-4 gene into mice and reconstitute Fe65-Tshcaspase-4 pathway in rodent, and clarify its involvement in AD progression by crossing the mice with AD model mice (APP/PSEN bigenic mice). We will also cross Tshz3 heterozygotes with APP/PSEN bigenic mice to clarify protective effects of Tsh3 to progression of AD pathology. We will compare AD progression patterns in these mice with those in humans using postmortem brain samples. Through these analyses, we will identify and validate molecular pathway that is involved in AD progression, which can be a potential therapeutic target.
Through this project, we will understand roles of risk factor and protective factor in progression of Alzheimer's disease. Based on this information, we may be able to devise new way of intervention to slow down the progression of the diseases.
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