Developing agents that selectively target the enzyme responsible for beta amyloid generation

The enzymatic mediated generation of beta amyloid from its larger parent molecule - the amyloid precursor protein (APP) - is a key event in the pathogenesis of Alzheimer's disease.

The enzyme responsible for this catalytic process is termed gamma secretase. Dys-regulation of APP processing leading to the overproduction and accumulation of beta amyloid leads to neuronal death / dysfunction, culminating in dementia.

The current therapeutic strategies aimed at inhibiting gamma secretase to lower beta amyloid levels have failed, most likely due to the activity of this enzyme on other proteins that are important cellular pathways and functions. This additional role for the enzyme is very important to consider when developing agents that reduce beta amyloid production.

The site will be identified using an array of molecular, biological and protein analysis techniques and will utilise an insect cell culture model of gamma secretase activity that we are currently developing.

The critical site will then be used to screen for peptide agents that selectively reduce beta amyloid production without affecting other enzyme products that are important in cellular function.

Overall, this project will provide valuable insight into the site(s) that are directly responsible for gamma secretase activity and thus provide more specific targets for development of rational therapeutic strategies.

Student Contributions

Honours student Kirsteen Lingoh, supervised by Professor Ralph Martins and Dr Giuseppe Verdile, contributed to this work and submitted her thesis in 2006. She passed her degree with first class honours.

International student Mr Sudarsan Krishnaswamy has enrolled in a PhD and is currently being supervised by Professor Ralph Martins and Dr Giuseppe Verdile to undertake this work.