ProfessorAnthony Don

Why do we lose myelin with ageing and how does this sensitize to dementia? 

Myelin is the insulating material that surrounds our neuronal axons, allowing for the rapid conduction of the electrochemical signals upon which our nervous system function depends. We know that demyelination has devastating consequences in diseases such as multiple sclerosis, leprosy, and inherited leukodystrophies, and it is very likely that the progressive loss of myelin after middle age leads to functional decline in our nervous system and, eventually, neurodegeneration. Age-dependent decline in myelin integrity and the function of our oligodendrocytes (the cells that make and maintain myelin) is also very likely to be a driving force in the pathogenesis of Alzheimer's disease and frontotemporal dementia. This project uses sophisticated stable isotope mass spectrometry to understand how myelin synthesis and turnover is affected by ageing, and how this contributes to neurodegeneration.

Altered brain lipid homeostasis in the etiology of Alzheimer's Disease.

This project tackles the tremendously important question of how genetic risk for Alzheimer's disease is related to altered brain lipid metabolism with ageing. It is well established that the major genetic risk determinants for Alzheimer's disease are genes encoding proteins that regulate brain lipid transport and turnover, however the underlying basis for how these gene variants affect Alzheimer's disease risk is not understood. More specifically, common variants in the APOE gene are the primary determinants of genetic risk for Alzheimer's disease, with the APOE4 allele increasing risk and the APOE2 allele decreasing risk relative to the common APOE3 allele. Our research is investigating how these gene alleles affect brain lipid turnover, and how this affects both myelin integrity and neuronal survival. We use very sophisticated mass spectrometry and mouse models to investigate these questions, as well as tissue from the NSW brain bank.

Control of myelination by the lipid signalling molecule S1P.

Our recent research has shown the essential role for the lipid signalling molecule S1P for remyelination following a demyelinating insult. In this project we use genetic mouse and cell culture models to investigate how S1P regulates oligodendrocyte function and myelination. We also investigate how pharmacological agonists of the S1P receptors, which are current multiple sclerosis drugs, mediate myelin and neuronal protection.

Developing new drugs to treat metabolic disease.

The lipid ceramide, particularly C16 ceramide produced by the enzyme ceramide synthase 6 (CERS6), is heavily implicated in the pathogenesis of insulin resistance, diabetes and cardiovascular disease. In fact, plasma ceramide screening is now gaining traction as a clinical diagnostic test for improved prediction of cardiovascular risk. This project involves the discovery and development of a new class of drugs to reverse insulin resistance and accelerate fatty acid metabolism by inhibiting ceramide synthesis in the liver, muscle, and adipose tissue.