Delineating The Interaction Between The Amyloid Precursor Protein Family And SorLA-LR11
Funder
National Health and Medical Research Council
Funding Amount
$749,022.00
Summary
The Alzheimer's disease Amyloid Precursor Protein (APP) is central to the cause of Alzheimer's disease (AD). It's metabolised into the neurotoxic amyloid beta (Abeta) peptide that is deposited in AD brains. The sorLA protein is a neuronal protein that interacts with APP and alters its metabolism into Abeta. This grant will study the interaction between APP and sorLA and define the APP binding site for sorLA which represents a potential drug target.
The Role Of Gonadotropins In Regulating The Production Of Alzheimer's Beta Amyloid
Funder
National Health and Medical Research Council
Funding Amount
$400,278.00
Summary
Currently, about 160,000 Australians suffer from dementia; of which 50-70% are Alzheimer's disease (AD) cases. AD is characterised clinically by memory and personality changes and pathologically by deposition of amyloid. Of particular importance in the disease pathogenesis, is a small molecule called beta amyloid, of which the overproduction is thought to be central to the development of AD. Changes in the levels of the reproductive hormones, particularly low levels of oestrogen during menopause ....Currently, about 160,000 Australians suffer from dementia; of which 50-70% are Alzheimer's disease (AD) cases. AD is characterised clinically by memory and personality changes and pathologically by deposition of amyloid. Of particular importance in the disease pathogenesis, is a small molecule called beta amyloid, of which the overproduction is thought to be central to the development of AD. Changes in the levels of the reproductive hormones, particularly low levels of oestrogen during menopause or testosterone during andropuase, has been associated with the increased risk of developing AD and in altering the levels of beta amyloid. Furthermore, menopause and andropause are also characterised by changes in other reproductive hormones such as the gonadotropins. High levels of the gonadotropins have also been associated with the increased risk of developing AD. Therefore it is important to identify how these changes modify the risk of developing AD. This study examines the role of the gonadotropins in regulating beta amyloid levels in cell culture and in an animal model for AD. Furthermore, this study will assess, in the animal model, the use of gonadotropin lowering agents to reduce levels of beta amyloid. The results from this study will provide important data on how reproductive hormones regulate beta amyloid. Further insight into these mechanisms will provide therapeutic or preventative strategies for AD.Read moreRead less
Characterisation Of Precursor Lesions In Colorectal Cancers With DNA Instability
Funder
National Health and Medical Research Council
Funding Amount
$60,190.00
Summary
It is now generally accepted that most colorectal cancers arise from previously benign lesions in the mucosal lining of the large bowel. These lesions are called adenomatous polyps. They have been extensively studied as have the cancers which evolve from them with regard to the type of cancer causing genetic changes they bear. Recently, it has been found that colorectal cancer is not a single disease in that there exists a subgroup comprising 15% of colorectal cancers which is an entirely differ ....It is now generally accepted that most colorectal cancers arise from previously benign lesions in the mucosal lining of the large bowel. These lesions are called adenomatous polyps. They have been extensively studied as have the cancers which evolve from them with regard to the type of cancer causing genetic changes they bear. Recently, it has been found that colorectal cancer is not a single disease in that there exists a subgroup comprising 15% of colorectal cancers which is an entirely different type wwith respect to genetic changes and biological behaviour. This subgroup contains cancers with a high level of microsatellite instability (MSI-high) and the cancers which comprise this group show none of the common genetic changes which can be demonstrated in both adenomatous polyps and the 85% of colon cancers which develop from them. The MSI-high colorectal cancers do however share some striking similarities to a type of polyp (hyperplastic) which has until quite recently been considered of little consequence. Our research group and others have shown an association with colorectal cancer in those patients in whom hyperplastic polyps are unusually large or numerous, especially if present in the right side of the large bowel, where the bulk of MSI-high colorectal cancers arise. The current proposal will investigate the hyperplastic polyp as a precursor lesion in the genesis of MSI-high cancers.Read moreRead less
MYOCARDIAL NEOVASCULARIZATION FOR ISCHEMIC HEART DISEASE USING BONE MARROW-DERIVED ANGIOBLASTS
Funder
National Health and Medical Research Council
Funding Amount
$577,400.00
Summary
Congestive heart failure remains a major public health problem. In Western societies heart failure is primarily the consequence of a previous myocardial infarction. We have recently identified certain cells in the bone marrow of adult humans that can cause new blood vessel development in the heart after infarction, protecting the heart muscle cells against death and preventing heart failure. Since the cardiovascular diseases that are most likely to benefit from treatments utilizing adult bone ma ....Congestive heart failure remains a major public health problem. In Western societies heart failure is primarily the consequence of a previous myocardial infarction. We have recently identified certain cells in the bone marrow of adult humans that can cause new blood vessel development in the heart after infarction, protecting the heart muscle cells against death and preventing heart failure. Since the cardiovascular diseases that are most likely to benefit from treatments utilizing adult bone marrow-derived endothelial progenitors, or angioblasts, predominantly affect aging individuals, critical questions that must be addressed are whether advanced age and-or progression of cardiovascular disease reduce the total numbers and-or the functional activity of such cells. In the current proposal we will investigate the relationship between increasing age or progression of ischemic heart disease and changes in the number and in vivo biologic properties of human angioblasts. Patients at various ages and stage of cardiovascular disease will be studied. Angioblast numbers will be quantitated in freshly obtained bone marrow cells. The ability of purified angioblasts to be targeted to the ischemic heart will be studied by labeling the angioblasts with a radioactive tracer and measuring tracer uptake in the heart at various time points after intravenous infusion of the cells. Finally, angioblast functional capacity will be evaluated using standard measurements of heart function before and at various time points after reinfusion of cells into the donor. In Aims 2 and 3 of this proposal we will focus our investigations on the potential use of angioblast therapy for reversal of established chronic heart failure in our animal models. Specifically, we will investigate whether induction of neovascularization results in cardiomyocyte regeneration and explore novel strategies to augment heart muscle regeneration by increasing angioblast trafficking to the damaged myocardium .Read moreRead less
Copper Homeostasis And APP-induced Neurodegeneration In Drosophila
Funder
National Health and Medical Research Council
Funding Amount
$381,223.00
Summary
Alzheimer s disease, a debilitating neurodegenerative disorder suffered by many of our elderly, is characterised by the presence of abnormal protein accumulations called plaques in the brains of affected patients. Plaques contain amyloid protein and also have high levels of the essential metals copper and zinc. Copper is needed for the formation of these protein aggregations and increases the toxic effects of amyloid, leading to the idea that copper-binding chemicals could be used to treat Alzhe ....Alzheimer s disease, a debilitating neurodegenerative disorder suffered by many of our elderly, is characterised by the presence of abnormal protein accumulations called plaques in the brains of affected patients. Plaques contain amyloid protein and also have high levels of the essential metals copper and zinc. Copper is needed for the formation of these protein aggregations and increases the toxic effects of amyloid, leading to the idea that copper-binding chemicals could be used to treat Alzheimer s disease. However experiments in animal models have produced conflicting results, some suggesting that increased copper levels protect against neuronal damage while others claim the opposite effect. Comparison of these studies is hampered by the different experimental systems used. We will clarify the role of copper in the progression of Alzheimer s disease using a simple insect model, the fly Drosophila melanogaster. Production of amyloid in Drosophila neuronal tissues produces a neurodegenerative effect similar to that seen in human brains, but in a matter of weeks rather than the years required in humans. We will combine production of amyloid with production of copper uptake and export proteins to investigate the effect of changing copper levels. We will also test the effect of increasing copper and other metals in the diet to see whether dietary levels are an important factor in disease progression. Finally, we will use the Drosophila model to test large numbers of metal binding compounds and drugs for ones that slow or halt the neuronal damage caused by amyloid production, identifying potential therapeutics for the treatment of Alzheimer s disease. This work will provide a vital and definitive clarification of the role of copper in the progression of Alzheimer s disease and potentially lead to the development of novel treatments for this disease that is rapidly becoming a major social and economic problem in the developed world.Read moreRead less
Alzheimer's disease is the most common form of dementia and is the fourth biggest killer in developed countries. This proposal concerns the biochemical investigation of a protein implicated in Alzheimer's disease. This work is expected to lead to the determination of the three-dimensional shape of the protein which will provide an understanding of what the protein's normal function is in the body and may form the basis for the design of drugs to combat the disease.
Gamma-secretase Complex: Molecular Characterization, And Moduation Of Enzymatic Activity
Funder
National Health and Medical Research Council
Funding Amount
$526,517.00
Summary
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 gam ....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.Read moreRead less
Molecular & Neuropsychological Predictive Markers Of Cognitive Decline.
Funder
National Health and Medical Research Council
Funding Amount
$429,500.00
Summary
Alzheimer's disease (AD) is a major cause of dementia in the elderly. As populations worldwide are living longer the prevalence of AD is predicted to rise markedly and in addition to the huge emotional burden on families the economic implications to the community at large is severe. Thus our aging veteran population and their spouses are particularly vulnerable to this devastating disease. Recent developments in AD research have resulted in a number of therapeutic strategies being undertaken wit ....Alzheimer's disease (AD) is a major cause of dementia in the elderly. As populations worldwide are living longer the prevalence of AD is predicted to rise markedly and in addition to the huge emotional burden on families the economic implications to the community at large is severe. Thus our aging veteran population and their spouses are particularly vulnerable to this devastating disease. Recent developments in AD research have resulted in a number of therapeutic strategies being undertaken with several of these now in phase 2 clinical trials. However for these treatments to be most effective early diagnosis is crucial. Currently, definite diagnosis is restricted to post-mortem examination of the brain for the presence of characteristic neuropathological features. This project proposes to identify individuals at high risk of developing cognitive decline leading to AD by using a battery of biochemical, genetic and neuropsychological markers. This study builds on our earlier work which followed a cohort of memory complainers and demonstrated that subjects in this group have lower cognitive scores and an increased frequency of the genetic risk factor, the e4 allele of apolipoprotein E. Follow up of this well studied cohort with more sensitive and extensive neuropsychological tests together with other genetic and biochemical markers will be important in identifying those risk factors that have positive predictive value for cognitive decline thereby contributing towards enhancing the therapeutic efficacy of current symptomatic and future drugs directed at the cause of AD.Read moreRead less