Gamma-secretase complex: molecular characterization, and moduation of enzymatic activity [ 2006 - 2008 ]

Research Grant

Researchers: Dr Genevieve Evin (Principal investigator) ,  Dr Janetta Culvenor

Brief description A small protein fragment terned A-beta accumulates as amyloid plaques in the brain of patients with Alzheimer's disease. A-beta is toxic, it causes degeneration of brain cells, and it is believed to be the primary cause of Alzheimer's disease. Therefore, developing strategies to reduce the amounts of A-beta in the brain constitutes a rational therapeutic approach. A-beta is produced from a precursor protein by two cleaving enzymes that operate in a sequential order: these are termed beta and gamma-secretases. Gamma-secretase carries out the second and final step in the release of A-beta peptide, and it is a determining factor since it can create A-beta fragments of different lengths and with different toxic properties. Our group studies the biochemical characteristics of gamma-secretase, and the factors that regulate its activity to uncover novel therapeutic leads. In this project we will 1) investigate the molecular composition of gamma-secretase using biochemical methods 2) study the importance of the two components of gamma-secretase, termed APH-1 and nicastrin, for the enzymatic activity 3) analyse the mechanism of mutations in the A-beta precursor protein that occur at or near the gamma-secretase site of cleavage and cause familial Alzheimer's disease 4) search for factors that regulate gamma-secretase activity using a genetic screen approach. The results of the proposed experiments will provide information to help design new therapeutic strategies for Alzheimer's disease, an illness that afflicts a large proportion of the ageing population and places a major socio-economic burden upon our society.

Funding Amount $AUD 526,517.61

Funding Scheme NHMRC Project Grants

Notes Standard Project Grant