Characterization Ol A Novel Covalently Cross -linked Abeta Peptide Dimer And Its Role In Alzheimers Disease.
Funder
National Health and Medical Research Council
Funding Amount
$553,236.00
Summary
Currently there are limited therapeutic treatments and no cure for Alzheimer's disease (AD). The key protein causing AD is called Abeta. Abeta peptides form dityrosine cross-linked dimers (when 2 peptides join together) and this is thought to be responsible for killing brain cells in AD. Therefore, this proposal will determine the role of Abeta dimers in relation to killing brain cells and the progression of AD through analysis of their biological and biochemical properties.
Amyloid Abeta In The Natural History Of Alzheimer's Disease
Funder
National Health and Medical Research Council
Funding Amount
$220,475.00
Summary
This grant is the continuation of a large series of experiments designed to uncover the basic causes of Alzheimer's disease. The focus is on closing some of the gaps in our knowledge of the natural history of Alzheimer's disease in relation to the deposition of the Abeta amyloid protein in the brain, which we believe plays a central role in the degeneration of nerve cells in this condition. The main questions we are tackling include: the feasibility of using assays of Abeta in the blood as a bio ....This grant is the continuation of a large series of experiments designed to uncover the basic causes of Alzheimer's disease. The focus is on closing some of the gaps in our knowledge of the natural history of Alzheimer's disease in relation to the deposition of the Abeta amyloid protein in the brain, which we believe plays a central role in the degeneration of nerve cells in this condition. The main questions we are tackling include: the feasibility of using assays of Abeta in the blood as a biological marker of Alzheimer's disease; whether better transgenic mouse models of Alzheimer's disease are required; whether the soluble forms of Abeta amyloid are the major species which cause neurotoxicity (in contrast to the insoluble forms which constitute the bulk of this protein in the Alzheimer's disease brain); and whether the intracellular or extracellular pathways of Abeta aggregation and toxicity are the key to understanding this disease. Increasing evidence suggests that the clearance of soluble forms of the Abeta protein from the brain may be a major therapeutic strategy. We therefore require further investigations of how these soluble forms of Abeta are generated in nerve cells, and how these forms exist in equilibrium with soluble and insoluble pools in the brain, cerebrospinal fluid, blood and other tissues of the body.Read moreRead less
The Physiological And Pathophysiological Roles Of Melanotransferrin
Funder
National Health and Medical Research Council
Funding Amount
$227,485.00
Summary
Melanotransferrin (MTf) is a membrane bound molecule that was originally identified in the malignant melanoma skin cancer and other tumours. Interestingly, MTf has many similarities to the serum iron-binding protein, transferrin, and initially MTf was thought to play a role in iron uptake by these cells. However, a series of studies by the applicant demonstrated that MTf did not play a major role in iron uptake by melanoma cells (Richardson et al. 1990, 1991a,b). In fact, most iron taken up by t ....Melanotransferrin (MTf) is a membrane bound molecule that was originally identified in the malignant melanoma skin cancer and other tumours. Interestingly, MTf has many similarities to the serum iron-binding protein, transferrin, and initially MTf was thought to play a role in iron uptake by these cells. However, a series of studies by the applicant demonstrated that MTf did not play a major role in iron uptake by melanoma cells (Richardson et al. 1990, 1991a,b). In fact, most iron taken up by these cells was via the binding of transferrin to the transferrin receptor. More recently, under the current NHMRC grant, we have been able to confirm and signficantly extend our previous studies to convincingly show that MTf is not involved in iron uptake by melanoma cells where it is expressed at very high levels (Richardson 2000 Eur. J. Biochem. 267 (in press). In addition, we showed that the expression of MTf in 50 human tissues was very different to transferrin and the transferrin receptor (TfR) that are well known to be involved in iron transport. For example, the TfR is expressed at high levels in tissues that require large amounts of iron eg. the placenta and bone marrow. In contrast, MTf was not expressed at high levels in these tissues, but was found in large amounts in unexpected locations such as the salivary gland. Furthermore, the expression of MTf was widespread through a variety of tissues, and in contrast to expectations, was found at higher levels in normal rather than fetal tissues. It is also intesting that MTf is found in the blood and brain of Alzheimer's disease patients. Our results suggest that MTf may play other unexpected roles apart from iron uptake. The present proposal will assess the roles of MTf in cellular functioning. This information will be very important in understanding the function of MTf in cancer cells, Alzheimer's disease and also in other tissues (eg. the salivary gland) where it is expressed at very high levels.Read moreRead less
The Mechanism, Predictive Value And Impact Of Apathy In Patients With Alzheimers Disease And Their Caregivers
Funder
National Health and Medical Research Council
Funding Amount
$542,370.00
Summary
Behavioural and psychological symptoms of dementia have been consistently associated with increased patients’ distress, and are considered by caregivers as the most difficult symptoms to manage. Apathy is the state of loss of motivation and emotional withdrawal that occurs in a high proportion of patients with Alzheimer’s disease. These patients require more management and support, given their reliance on others to schedule their activities and initiate behaviours even when they are still capabl ....Behavioural and psychological symptoms of dementia have been consistently associated with increased patients’ distress, and are considered by caregivers as the most difficult symptoms to manage. Apathy is the state of loss of motivation and emotional withdrawal that occurs in a high proportion of patients with Alzheimer’s disease. These patients require more management and support, given their reliance on others to schedule their activities and initiate behaviours even when they are still capable of performing the activities. In spite of the high frequency of apathy in dementia and the high potential of negative effects on patients and caregivers, little is known about the cause of this phenomenon, its potential influence upon the long-term progression of Alzheimer’s disease, and on its impact upon caregivers’ emotional well-being. The main aim of our proposal is to examine the mechanism, clinical relevance and impact of apathy in Alzheimer’s disease. More specifically, we will determine whether apathy predicts more severe depression, increasing motor problems, and a faster progression of cognitive and functional problems. Using state-of-the-art neuroimaging techniques we will examine the association between apathy and abnormalities in specific brain regions. Finally, we will examine whether caregivers of patients with apathy have relatively more severe emotional problems, a higher care giving burden and poor quality of life.Read moreRead less
A Multicentre Randomised Clinical Trial Of Physical Activity For The Treatment Of Patients With Alzheimers Disease
Funder
National Health and Medical Research Council
Funding Amount
$773,752.00
Summary
The number of older adults living with Alzheimer's disease (AD) will increase from 26.6 million to 106.2 million by 2050. In the absence of curative treatment options it is important to focus on non-pharmacological interventions such as physical activity. We propose to investigate whether a home-based physical activity program of 24 weeks for patients with AD can successfully decrease the rate of cognitive and functional declince and improve quality of life and psychological well-being.
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
The Modulation Of Metals To Improve The Cognitive And Pathological Features Of Alzheimers Disease
Funder
National Health and Medical Research Council
Funding Amount
$436,238.00
Summary
This proposal will characterise the effects of a novel therapy for the treatment of Alzheimer's disease. Our preliminary data show that this approach can affect both the onset and progression of the disease, as well as the symptoms that characterise it. Thus, a thorough assessment of these effects and this drug target provides a tangible movement towards a truly effective treatment for Alzheimer's disease.
Sydney Multisite Intervention Of LaughterBosses And ElderClowns (SMILE): An RCT Of Humour Therapy In Residential Care
Funder
National Health and Medical Research Council
Funding Amount
$852,237.00
Summary
Sydney Multisite Intervention of LaughterBosses and ElderClowns (SMILE) is a trial of humour therapy. About 400 residents from 36 hostels and nursing homes will be randomly assigned to receive the SMILE treatment or usual care. ElderClowns will visit weekly, and staff volunteers will be trained to be LaughterBosses and bring humour to daily care routines. SMILE will evaluate whether humour therapy improves resident quality-of-life and mood, and reduces staff burnout and turnover.