Grant: Operating Grant

Deposition of amyloid beta protein (Abeta) in the brain is a central pathological feature of Alzheimer's disease (AD). Proteolytic processing of beta-amyloid precursor protein (APP) at the beta site by the Beta site APP Cleaving Enzyme 1 (BACE1), the beta-secretase in vivo, is essential to generate Abeta. BACE1 gene expression is tightly regulated and it shows tissue specificity with its enzymatic activity mainly in central nervous system. Increased beta-secretase activity was reported in the cortex of AD patients and abnormal BACE1 gene regulation links vascular factors to AD. We propose to continue studying the molecular mechanisms of BACE1 gene regulation and its role in AD. Our working hypothesis is that transcriptional dysregulation of the human BACE1 gene plays an important role in the development of AD. This proposal seeks to further examine transcriptional regulation of the BACE1 gene and the mechanism underlying the 5'UTR regulating BACE1 translation initiation, as well as their role in the development of AD. Results from this proposal will thoroughly characterize the transcriptional regulation of the human BACE1 gene, and the role of abnormal gene transcription in the development of AD. It will provide much needed information regarding the cell signal transduction in APP processing and has an important pharmaceutical implication in AD therapy.