Very broadly speaking, our research is focused on the role that lipids (which are fats such as cholesterol) play in regulating both the normal function of neurons as well as their demise in diseases such as Alzheimer's disease and Parkinson's disease. A large amount of our research is focused at a very basic level that is defining at the molecular and cellular level how lipids (which are components of all cell membranes) can modify the pathways that lead to neuronal death. Our research also extends into studies of mice that are genetically modified in order to exhibit characteristics of Alzheimer's disease and atherosclerosis. These latter studies permit us to develop novel pharmacological approaches that will enable us to more effectively treat neurological and vascular diseases in humans.
Alzheimer's disease (AD) prevalence is rising and the contributing factors are poorly understood. Our recent research shows that cholesterol regulates the production of neurotoxic amyloid-beta peptide. We are studying a class of proteins, ABC transporters, that we have shown regulate neuronal cholesterol levels and amyloid-beta production. Our research utilises isolated brain cells, human brain tissue and genetically engineered mice in order to define how cholesterol influences AD and identify new treatment options. Overall this research will provide a framework for the development of novel and realistic approaches to treat AD. People with advanced AD often can't remember their own names or the names or faces of their family. This research is significant as there is an increasing prevalence of AD in our community and it has the potential to identify targets for curative or at least disease modifying treatments. The data generated in this project is urgently required to better understand the link between cholesterol transport and AD pathology Atherosclerosis is an important contributor to heart attack, stroke and vascular dementia and accounts for ~50% of all deaths in developed countries. We have shown that specific members of a family of lipids called sphingolipids promote atherosclerosis and we are currently testing novel therapeutic approaches (inhibiting synthesis of specific sphingolipids) to prevent atherosclerosis in a disease-susceptible mouse model. This research has the potential to identify a new approach to treat atherosclerosis in humans.
There are currently six major projects underway in the Garner Group. These projects all have distinct aims and objectives but the technologies and experimental approaches are inter-related in some cases. In Project 1 we are examining how membrane lipids regulate the production of a toxic peptide (amyloid-beta) that is thought to contribute to Alzheimer’s disease. In this study we are using lipid syntheses inhibitors as novel regulators of amyloid-beta production. (see also Interaction of cholesterol and glycosphingolipids (GSLs) in lipid rafts and impact on neuronal amyloid-beta peptide formation). In Project 2 we are examining the role that a family of membrane proteins called ABC transporters play in amyloid-beta production. These studies are utilising isolated brain cells as well as mice that have been genetically modified to exhibit Alzheimer’s disease-like pathology (see also link to Regulation of neuronal cholesterol balance and amyloid-beta production by ATP-binding cassette (ABC) transporters). In Project 3 we are investigating the function of a cholesterol transport protein known as apoE in terms of its ability to control lipid balance in neurons and other brain cell types and also the role that it may play in Alzheimer’s disease. The apoE protein is present in the brain and in human can exist in three main forms known as apoE2, apoE3 and apoE4. The apoE4 form is a risk factor for Alzheimer’s disease but the reasons for this are unknown. Our research aims to shed light on this important unresolved question. (see also link to Understanding the function of apolipoprotein-E in neurobiology and neurodegeneration). In Project 4 we are determining that major factors responsible for controlling the level of a protein called alpha-synuclein in neurons. It is established that increases in the concentration of neuronal alpha-synuclein are correlated with cell death in Parkinson’s disease and we have evidence that specific oxidised forms of cholesterol may increase its production. (see also link to Regulation of neuronal alpha-synuclein expression). In Project 5 we are examining the role of intracellular organelles called lysosomes in amyloid-beta production. The role that ABC transporters may play in regulating lysosomal lipid composition is a major focus of this project. (see also link to Function of ABCA and G transporters in regulation of lysosomal membrane lipids and implications for amyloid-beta mediated neurodegeneration). In Project 6 we are developing new pharmacological approaches to inhibit atherosclerosis. The research is focused on understanding the role that a specialised family of lipids known as sphingolipids play in atherosclerosis which is a disease of the arteries characterised by lipid accumulation and thickening of the artery wall which can result in reduced blood flow to the heart and brain. (see also link to Targeting the sphingolipid biosynthetic pathway to treat atherosclerosis).