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
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
Truncating Presenilin Mutations And Their Effects On Gamma-secretase Activity, Tau And Beta-catenin
Funder
National Health and Medical Research Council
Funding Amount
$414,005.00
Summary
Alzheimer's disease (AD) and cancer are increasingly important both in terms of human suffering and the burden of care it imposes on society and the economy. Sporadic (non-inherited) AD is the most common form of dementia but is poorly understood. The PRESENILIN genes, PSEN1 and PSEN2, are the major sites for mutations causing inherited AD and are also implicated in cancer. Using the zebrafish embryo model we have discovered that, contrary to current thought, mutations that truncate presenilin p ....Alzheimer's disease (AD) and cancer are increasingly important both in terms of human suffering and the burden of care it imposes on society and the economy. Sporadic (non-inherited) AD is the most common form of dementia but is poorly understood. The PRESENILIN genes, PSEN1 and PSEN2, are the major sites for mutations causing inherited AD and are also implicated in cancer. Using the zebrafish embryo model we have discovered that, contrary to current thought, mutations that truncate presenilin proteins potently suppress normal presenilin activity. (They are so called, dominant negatives). This means that they are lethal for embryo development and explains why such mutations have never been found in inherited AD. Notably, this discovery could only be made using a subtle form of gene manipulation that is possible in zebrafish embryos. Our work has also established the first assay for the non-apoptotic (non-cell death) function of PSEN2 and has shown that PSEN2 activity is inhibited by truncated PSEN1. This is the first indication of possible interaction between PSEN1 and PSEN2 proteins at normal physiological expression levels. Loss of presenilin activity promotes cancer. Truncated presenilin proteins could be produced by errors in gene transcription (aberrant transcript splicing) common in cancerous cells. This suggests that truncated, dominant negative forms of presenilin produced through aberrant splicing (or mutation in precancerous cells) might be common in tumour formation. The proposed research will define the region of PSEN1 in which truncation leads to dominant negative activity. This will allow further examination of the role of presenilins in the cell signalling pathways involved in AD and cancer. We will also investigate the role that age-related truncation of presenilins in human cells can play in the formation of sporadic AD. This may reveal a common molecular link between the inherited and sporadic forms of this disease.Read moreRead less