Grant: China-Canada Joint Health Research Initiative

Deposition of amyloid beta protein (Abeta) in the brains is one of the hallmarks of Alzheimer's Disease (AD) pathogenesis. Abeta is generated from a larger beta-amyloid precursor protein (APP) by beta-secretase and gamma-secretase cleavages. Gamma-secretase activity was catalyzed by a PS1-containing macromolecular complex. This high molecular weight complex also requires nicastrin, anterior pharynx-defective 1, and presenilin enhancer 2 for its enzymatic activity. Recently, TMP21 was identified as a new member of the presenilin associated complex. Knock down of TMP21 with siRNA caused an increase in Abeta40 and Abeta42 but no change in Notch cleavage. However, the biological function and its role in AD pathogenesis have not been well defined. The ongoing collaboration between Dr. Kun Xia's lab at The State Key Lab of Medical Genetics of China and Dr. Weihong Song's lab at The University of British Columbia discovered that that the TMP21 is ubiquitinated and its degradation is mediated by a proteasome pathway and NFAT plays a pivotal role in regulation of TMP21 expression. Furthermore we discover a novel intron-4 SNP in TMP21 gene associated with AD. Our working hypothesis is that alteration of TMP21 expression plays an important role in AD pathogenesis. This collaborative proposal seeks to continue utilizing the strengths of two complementary labs in Canada and China to define the function of TMP21 and examine the genetic association of TMP21 with AD and its role in AD pathogenesis.