Targeting Inflammatory Mechanisms In Alzheimer's Disease.
Funder
National Health and Medical Research Council
Funding Amount
$392,750.00
Summary
Alzheimer s disease accounts for the majority of dementia cases and is the most common cause for nursing home requirements in Australia. It is not a disease that is confined to old age as it can also affect individuals in their 20s and 30s. There is currently no cure for Alzheimer's disease, largely because the underlying cause is unknown. Deposition of the amyloid-beta protein within the brain of Alzheimer's disease patients is thought to be responsible for the neuronal cell loss which underlie ....Alzheimer s disease accounts for the majority of dementia cases and is the most common cause for nursing home requirements in Australia. It is not a disease that is confined to old age as it can also affect individuals in their 20s and 30s. There is currently no cure for Alzheimer's disease, largely because the underlying cause is unknown. Deposition of the amyloid-beta protein within the brain of Alzheimer's disease patients is thought to be responsible for the neuronal cell loss which underlies the dementia. However, amyloid-beta protein deposition can occur in the absence of dementia and in the asbence of significant neuronal cell loss, suggesting that an alternative mechanism of neurotoxicity exists. Inflammation is a consistent feature of the Alzheimer's disease brain. We have preliminary evidence to suggest that inflammation is responsible for the neurotoxicity in Alzheimer's disease. We have recently observed a significant inflammatory response surrounding an unidentified protein in the brains of individuals with a familial form of Alzheimer's disease due to a genetic mutation. This inflammatory response is not associated with the significant amyloid-beta protein deposition seen in these cases suggesting that a novel potent inflammatory stimulus exists. Furthermore, these cases have greater neuronal cell loss and a shorter disease duration, both indicators of increased neurotoxicity. The present study is designed to determine the toxicity of inflammation and the stimulus driving this response in the Alzheimer's disease brain using tools for protein and gene analysis, as well as determining the extent of inflammation-mediated toxicity on neuronal cells grown in culture. Only by addressing these aims can we concentrate on developing safe and effective therapeutic strategies to prevent or treat the disease process.Read moreRead less
Functional Studies On A Neuroprotective Activity Of The Amyloid Precursor Protein Of Alzheimer S Disease.
Funder
National Health and Medical Research Council
Funding Amount
$160,475.00
Summary
Alzheimer's disease is a major health problem of the elderly. With our aging population living longer, this presents enormous economic and social pressures. Research into the mechanism of Alzheimer's disease is therefore of immediate importance. In this study we are trying to determine the relationship between proteins involved in the disease process. In particular we are studying the amyloid precursor protein (APP). APP has both therapeutic as well as disease causing actions. It gives rise to t ....Alzheimer's disease is a major health problem of the elderly. With our aging population living longer, this presents enormous economic and social pressures. Research into the mechanism of Alzheimer's disease is therefore of immediate importance. In this study we are trying to determine the relationship between proteins involved in the disease process. In particular we are studying the amyloid precursor protein (APP). APP has both therapeutic as well as disease causing actions. It gives rise to the toxic amyloid peptide Abeta which is responsible for disease. However APP can also inhibit Abeta toxicity thus controlling cell death. We are studying how APP is able to modulate the neurotoxic activity of Abeta. These studies will identify key aspects of the disease pathway and hopefully lead to treatment strategies.Read moreRead less
The Kynurenine Pathway Chemokines And MIC-1 In The Pathogenesis Of AIDS Dementia Complex.
Funder
National Health and Medical Research Council
Funding Amount
$241,980.00
Summary
This proposal will examine the mechanisms by which HIV and other brain disorders such as encephalitis damage the brain. Further understanding of the biochemical pathway involved will lead to the possibility of novel drug therapy for these disorders.
Anatomical Substrates For Primate Executive Cortical Function
Funder
National Health and Medical Research Council
Funding Amount
$362,820.00
Summary
When studying the brain, many have been tempted to look for similarities in organization of cells and circuitry in different regions involved in various processes. While, at a first approximation, this may be a reasonable approach to understand how the brain works, it also ignores what makes the brain so complex: the diversity in its structure. In the late 19th, and early 20th, centuries, pioneering anatomists seized on the diversity in structure of the human brain. The study of cortical circuit ....When studying the brain, many have been tempted to look for similarities in organization of cells and circuitry in different regions involved in various processes. While, at a first approximation, this may be a reasonable approach to understand how the brain works, it also ignores what makes the brain so complex: the diversity in its structure. In the late 19th, and early 20th, centuries, pioneering anatomists seized on the diversity in structure of the human brain. The study of cortical circuitry that underlies the diversity in cortical processing reached a zenith and there was a renaissance in understanding of brain function. These researchers were, however, limited by techniques available to them at the time. With the advent of new methodologies which allowed scientists to explore individual connections between cells (synapses), to probe structure and transmission across synapses, and to record from live neurones, new and exciting discoveries were made. However, these methodologies are highly time consuming and studies became necessarily more focussed. As a result, there was a tendency in the later half of the 20th century to extrapolate findings from one cortical area to cortex in general. Even more precarious, anatomical and functional findings in highly specialized sensory cortex of one species were projected to other distantly related species. Such thinking lead to a dark age in neuroscience. It became widely accepted that there exists a canonical circuit. Consequently, differences in function between different cortical areas were attributed solely to the source of their projections. The central thesis of this project is to study aspects of cell structure and cortical circuitry in the prefrontal lobe. We hope that the project will provide another step in the pathway that leads to understanding the mind.Read moreRead less
Regulation And Substrate Identification Of Parkinsons Disease Causative Leucine-rich Repeat Kinase 2 (LRRK2)
Funder
National Health and Medical Research Council
Funding Amount
$699,456.00
Summary
Parkinson's disease afflicts 100,000 Australians. Mutations in the recently identified enzyme Leucine-rich Repeat Kinase-2 are a common cause of Parkinson's disease. This project will use biochemical methods to understand how this brain enzyme causes disease by investigating its enzymology, modes of regulation, and target substrates that it modifies by addition of phosphate groups. Characterization of this enzyme will facilitate design of inhibitors to slow the course of Parkinson's disease.
Comparative Analysis Of Novel Transgenic Mouse Models For Brain And Islet Amyloidoses
Funder
National Health and Medical Research Council
Funding Amount
$468,119.00
Summary
We aim to understand what two highly prevalent diseases, the brain disorder Alzheimer's disease (AD) and the metabolic disorder Type 2 Diabetes mellitus (DM), have in common. Through understanding pathogenesis and the development of novel transgenic models our long-term research goal is to identify new drug targets, to develop screening assays and to patent new findings. Collectively, this hopefully leads to AD and DM drugs and reduces the socio-economic burden of both debilitating diseases.
The Influence Of Gamma-secretase Complex Subunits On The Production Of Alzheimer Amyloid Peptides
Funder
National Health and Medical Research Council
Funding Amount
$641,540.00
Summary
Alzheimer's disease is a devastating illness of the aged population and represents a major socio-economic problem in Australia. There is no cure or effective treatment for the illness. A toxic protein fragment known as Abeta amyloid accumulates in the brain of the diseased patients. This is produced by an enzyme called gamma-secretase. This project will investigate different forms of gamma-secretase to gain information useful for developing Alzheimer-specific drugs with little side-effects.
The Contributions Of Different Sources Of Calcium To The Induction Of Long Term Potentiation
Funder
National Health and Medical Research Council
Funding Amount
$267,750.00
Summary
When we make memories, we alter the strength of synaptic connections between nerve cells.These changes are particularly marked in the hippopcampus ; a region of the brain involved in the formation of memories. The strength of a synaptic connection is altered if it activates a neurone sufficiently to cause a rise in the level of calcium ions. Calcium can be derived from several sources within the neurone. This project aims to assess the relative importance of these different sources of calcium in ....When we make memories, we alter the strength of synaptic connections between nerve cells.These changes are particularly marked in the hippopcampus ; a region of the brain involved in the formation of memories. The strength of a synaptic connection is altered if it activates a neurone sufficiently to cause a rise in the level of calcium ions. Calcium can be derived from several sources within the neurone. This project aims to assess the relative importance of these different sources of calcium in inducing increases in synaptic strength.Read moreRead less
Gene-environment Interactions And Experience-dependent Plasticity In The Healthy And Diseased Cerebral Cortex
Funder
National Health and Medical Research Council
Funding Amount
$249,250.00
Summary
Huntington's disease (HD) is a devastating illness in which movement disorders (including chorea) and mental problems progress for 10-20 years after onset, and inevitably lead to death. HD is caused by an expansion in a repeating segment of DNA in a single gene and is inherited by 50% of the offspring of sufferers. Despite this strong genetic factor, we have recent evidence from a mouse model, in which the human HD gene mutation has been inserted into the mouse genome, supporting a role for envi ....Huntington's disease (HD) is a devastating illness in which movement disorders (including chorea) and mental problems progress for 10-20 years after onset, and inevitably lead to death. HD is caused by an expansion in a repeating segment of DNA in a single gene and is inherited by 50% of the offspring of sufferers. Despite this strong genetic factor, we have recent evidence from a mouse model, in which the human HD gene mutation has been inserted into the mouse genome, supporting a role for environmental factors in disease onset and progression. Following on from our work showing that environmental enrichment delays disease and progression in this mouse model of HD, we are using experimental manipulations of the environment to examine effects on brain degeneration and behaviour. This project aims to investigate gene-environment interactions in HD, focusing on dysfunction of neurons in the cerebral cortex. The combination of behavioural, physiological, anatomical and molecular analysis of HD mice will bring us closer to a comprehensive understanding of HD. This will have implications for the development of new therapies for HD. Our environmental enrichment paradigm may also lead to development of occupational therapy strategies for HD and other neurological disorders. There are at least ten other fatal brain disorders which are caused by the same DNA repeat expansion in other genes. New insights into HD will therefore have implications for the understanding and development of therapeutics for these other DNA repeat expansion brain diseases. Furthermore, another devastating brain disorder which, like HD, involves abnormal protein interactions and dysfunction of the cortex, is Alzheimer's disease. Understanding HD may therefore also have implications for our understanding of Alzheimer's disease. Additionally, analysing control mice in this project will provide new information on mechanisms of plasticity in the normal cortex, which may underlie learning and memory.Read moreRead less