Regulation of the BACE1 gene expression in Alzheimer's Disease pathogenesis

Alzheimer's disease (AD) is the most common neurodegenerative disorder leading to dementia, affecting approximately 10 per cent of the Canadian population over the age of 65. One of the pathological hallmarks of AD is increased deposition of the beta-amyloid protein, which forms amyloid plaques in the brains of AD patients. This is caused by dysfunction of the BACE enzyme, which regulates processing of the amyloid precursor protein to generate beta-amyloid proteins. Levels of the BACE enzyme have been shown to be elevated in Alzheimer’s. Philip Ly is interested in studying the underlying molecular mechanisms regulating the BACE enzyme expression and activity. He is studying a region of the BACE gene called the BACE promoter. This region has been demonstrated to be important for BACE expression. However, the regulations at the level of BACE gene transcription – the first step in the expression of the genetic information – remain elusive. Using a series of molecular and biochemical approaches, Ly is examining the transcriptional controls that regulate BACE gene expression in neurons. He is also examining if specific mutations in these transcription factors affect BACE expression and contribute to AD pathogenesis. Ly’s research will be the first to thoroughly characterize the transcriptional regulation of the BACE1 and the role of abnormal gene expression in AD pathogenesis. In addition to providing much needed information regarding signal transduction in amyloid precursor protein processing, these studies have important pharmaceutical implications, such as potential development of BACE enzyme inhibitors to improve treatment of Alzheimer's disease.