DUAL AND MULTIPLE PROTEINOPATHIES IN NEURODEGENERATIVE DEMENTIAS – RISK FACTORS, PROGNOSTIC INDICATORS AND CLINICAL RAMIFICATIONS
Funder
National Health and Medical Research Council
Funding Amount
$604,644.00
Summary
Dementia is the umbrella term used to refer to a number of different clinical presentations,each associated with distinct histopathological signatures of protein aggregates and spread.However, converging evidence now suggests the common co-occurences of dual/multiple proteinopathies across dementia syndromes.The present study will identify the clinical ramifications and factors that are most predictive for such proteinopathies in a large cohort of longitudinally-studied patients with dementia.
Cannabidiol (CBD): A Novel Therapeutic For Alzheimer's Disease.
Funder
National Health and Medical Research Council
Funding Amount
$775,005.00
Summary
Current drugs do not stop or reverse the progression of Alzheimer’s disease (AD). Also, brains of AD patients show a number of biological changes and effective drugs should target those together. Cannabidiol (CBD) has such abilities when tested in AD cell models. We found that CBD can also prevent and reverse memory deficits in AD mice. We propose to provide convincing preclinical evidence for the benefits of CBD for human AD therapy and to define mechanisms involved.
Down syndrome (DS) individuals have 3 copies of chromosome 21. I am proposing to do my PhD to investigate the role of a gene existing on chromosome 21 called Intersectin 1. This gene, when over-expressed might be responsible for manifestation of intellectual impairment in Down syndrome. I will be examining the consequence of altered/over-expression of this gene in receptor trafficking, cell signalling and histology of the brain to identify the differences between affected individuals and the nor ....Down syndrome (DS) individuals have 3 copies of chromosome 21. I am proposing to do my PhD to investigate the role of a gene existing on chromosome 21 called Intersectin 1. This gene, when over-expressed might be responsible for manifestation of intellectual impairment in Down syndrome. I will be examining the consequence of altered/over-expression of this gene in receptor trafficking, cell signalling and histology of the brain to identify the differences between affected individuals and the normal population.Read moreRead less
Differential Regulation Of Human Tyrosine Hydroxylase Isoforms And The Development Of Parkinson's Disease
Funder
National Health and Medical Research Council
Funding Amount
$325,591.00
Summary
Parkinson's disease is a common neurodegenerative disease whose major feature is loss of a dopamine containing nerves in a part of the brain called the substantia nigra. Loss of nerves within the substantia nigra is not uniform, but firstly and primarily affects the ventral cells, suggesting that particular dopaminergic neurons are more vulnerable to the disease process. A key to understanding Parkinson's disease would be to work out why these cells are more susceptible to degeneration than othe ....Parkinson's disease is a common neurodegenerative disease whose major feature is loss of a dopamine containing nerves in a part of the brain called the substantia nigra. Loss of nerves within the substantia nigra is not uniform, but firstly and primarily affects the ventral cells, suggesting that particular dopaminergic neurons are more vulnerable to the disease process. A key to understanding Parkinson's disease would be to work out why these cells are more susceptible to degeneration than other dopaminergic cells in the brain. Tyrosine hydroxylase controls the rate of dopamine synthesis. Humans are unique in that they contain four isoforms of tyrosine hydroxylase and therefore they have the potential to alter the regulation of dopamine synthesis in ways that other species do not. Recent developments in our laboratories have suggested that particular isoforms of tyrosine hydroxylase may have either a role in the susceptibility of dopaminergic neurons to degeneration in Parkinson's disease or a role in the timing of the symptoms of the disease. We have demonstrated differences in the distribution of the human TH isoforms within the substantia nigra, with certain isoforms being more prevalent in the susceptible ventral cells. We have also shown that there are major differences in the regulation of the four human tyrosine hydroxylase isoforms. Some isoforms will be more sensitive to conditions that occur with high frequency stimulation of neurons and some to low frequency sustained stimulation. This would provide a mechanism by which differential distribution of the human TH isoforms would result in altered dopamine synthesis in different parts of the human brain and this may in turn lead to either increased susceptibility to, or earlier appearance of symptoms of, Parkinson's disease.Read moreRead less
Controlling The Development And Function Of Hindbrain Commissures In Vertebrate Animals: The Role Of Robo3 Receptor
Funder
National Health and Medical Research Council
Funding Amount
$393,834.00
Summary
Commissural axons connect and coordinate activity between neurons of the left and right sides of the central nervous system. In the forebrain, formation of commissural axons is determined by guidance factors at the midline between the two hemispheres, and abnormalities in guidance can cause developmental malformations. The aims of this project are to elucidate function of the Robo/Slit family of molecules in regulating axon guidance of commissural neurons, particularly in the corpus callosum.
How critical is the inflammatory response in senile plaque formation in a mutant APP transgenic mouse model? The aims of this project is to examine the brains of mice genetically engineered to produce a human mutant form of insoluble beta amyloid protein known to play a critical role in the development of Alzheimer's disease (AD). If the "trigger" for AD is an inflammatory reaction, then the relevant examination of the early stages of senile plaque formation in these animals could lead to pharma ....How critical is the inflammatory response in senile plaque formation in a mutant APP transgenic mouse model? The aims of this project is to examine the brains of mice genetically engineered to produce a human mutant form of insoluble beta amyloid protein known to play a critical role in the development of Alzheimer's disease (AD). If the "trigger" for AD is an inflammatory reaction, then the relevant examination of the early stages of senile plaque formation in these animals could lead to pharmaceutical intervention to delay the development of this debilitating disease. A 5 year delay would significantly reduce the number of people with AD, not only adding years of improved quality of life, but also saving hundreds of millions of Australian dollars in health costs.Read moreRead less
Microparticles as effectors of microvascular alterations in brain inflammation. Cerebral malaria (CM) kills many children worldwide, but we do not understand why their small blood vessels in the brain become obstructed. We found that tiny elements detached from cell membranes, called microparticles (MP), are dramatically elevated in the blood during CM. Our results strongly suggest that these MP are important in CM development. We have found that some drugs block the release of MP and the stick ....Microparticles as effectors of microvascular alterations in brain inflammation. Cerebral malaria (CM) kills many children worldwide, but we do not understand why their small blood vessels in the brain become obstructed. We found that tiny elements detached from cell membranes, called microparticles (MP), are dramatically elevated in the blood during CM. Our results strongly suggest that these MP are important in CM development. We have found that some drugs block the release of MP and the stickiness of malaria parasites to blood vessels. Our project will tackle the conditions of MP production and define new drugs to prevent it. It also will explain how the brain becomes affected by high numbers of MP. Our results will cast new light on why the brain functions abnormally when its blood vessels become modified.Read moreRead less
Neurexin And Neuroligin: A Code For Synaptic Development
Funder
National Health and Medical Research Council
Funding Amount
$349,590.00
Summary
As soon as we are born, we interpret our world through our senses, learn new information and lay down memory. These processes require molecules that connect neurons together. Mutations in genes encoding these molecules result in incorrect wiring of the brain and lead to mental disorders such as autism and schizophrenia. Using simple insect models, our project aims to unravel the fundamental mechanisms of how these molecules function in the brain and how their interaction controls behaviour.
Interleukin-6 -gp130 Signaling And Actions In The CNS
Funder
National Health and Medical Research Council
Funding Amount
$549,092.00
Summary
Interleukin-6 (IL-6) is a member of a family of cytokine proteins that may be causative factors in many neurological disorders where they are involved in diverse processes including inflammation, neuronal injury and repair. In this project we will study how IL-6 affects the brain to bring about these outcomes. The results of this work will advance our understanding of how members of this cytokine family function and how they contribute to neurological disease.
Identification And Characterisation Of A Novel Parkinson's Disease Gene
Funder
National Health and Medical Research Council
Funding Amount
$556,313.00
Summary
Parkinson’s disease (PD) is a complex neurological condition affecting 100,000 Australians. The primary clinical features of PD result from the selective loss of a specific type of neuron. These neurons make up less than 1% of the over 50 million neurons within the brain, and it is currently unclear why they are preferentially lost during disease development. We have identified a novel gene that causes early onset parkinsonism. This study will characterise the gene and determine what role it pla ....Parkinson’s disease (PD) is a complex neurological condition affecting 100,000 Australians. The primary clinical features of PD result from the selective loss of a specific type of neuron. These neurons make up less than 1% of the over 50 million neurons within the brain, and it is currently unclear why they are preferentially lost during disease development. We have identified a novel gene that causes early onset parkinsonism. This study will characterise the gene and determine what role it plays in the development of PD.Read moreRead less