Alzheimer's Disease And Related Disorders: Mechanism Of Tau Pathology In Established And Novel Transgenic Animal Models
Funder
National Health and Medical Research Council
Funding Amount
$423,017.00
Summary
Alzheimer's disease (AD) is a devastating neurodegenerative disease for which no cure is available. It affects more than 15 million people worldwide. There are estimates that by 2040, approximately 500'000 Australians will suffer from AD, with associated health costs of about 3% of the GDP. AD is characterized by two major brain lesions, beta-amyloid plaques and neurofibrillary tangles (NFTs). The latter contain a protein called tau which is in a fibrillar and highly phosphorylated state. We wer ....Alzheimer's disease (AD) is a devastating neurodegenerative disease for which no cure is available. It affects more than 15 million people worldwide. There are estimates that by 2040, approximately 500'000 Australians will suffer from AD, with associated health costs of about 3% of the GDP. AD is characterized by two major brain lesions, beta-amyloid plaques and neurofibrillary tangles (NFTs). The latter contain a protein called tau which is in a fibrillar and highly phosphorylated state. We were the first to establish a transgenic animal model of pre-tangles and, together with Dr. Hutton's laboratory, of NFT formation. We could further show that injections of beta-amyloid into brains of our tau mutant mice enhanced the NFT pathology in these mice. By Functional Genomics we identied genes and proteins, which are induced by tau expression. The specific aim of this proposal is to determine whether oxidative stress enhances the tau pathology in our tau mutant mice and whether distinct brain areas are particularly susceptible to this kind of stress. The reason for addressing this question is twofold: On the one hand, we have found in our mice that reactive oxygen species are increased, secondly it is known that some brain areas in the AD brain are degenerating, whereas others are not. A second aim is to develop novel tau transgenic models where individual interactions of tau with cellular proteins are disturbed. Finally, we want to determine whether the two kinases BMX and FAK and the phosphatase PPV regulate tau phosphorylation in vivo. Together, we hope that our efforts lead to a better understanding of the pathogenic mechanisms in AD and related disorders. As pathocascades are likely to be shared between a range of diseases, these findings may also contribute to other fields of research, such as Parkinson's disease. Ultimately, these efforts will assist in the development of a safe treatment of AD.Read moreRead less
Problems in learning, memory and other complex mental processes are common to many brain disorders. This project will study the impact of mutations on a family of genes reported in autism and schizophrenia, on complex cognitive behaviours using novel behavioural technologies. This will not only shed fundamental insights into the specific mental processes regulated by these genes and their role in disease, but importantly provide novel targets for the development of therapies.
The majority of stroke results from focal brain infarction, followed by substantial secondary excitotoxic damage in the surrounding areas. Tau has been shown to contribute to excitotoxicity and neurodegeneration in mouse models of Alzheimer’s disease (AD). Preliminary data show that tau reduction also protects against excitotoxic damage after experimental stroke. We aim to dissect the molecular mechanisms of stroke using a tau-deficient mouse model.
New Projection Neurons Are Added To The Brain Throughout Life – Identifying Their Source And Function.
Funder
National Health and Medical Research Council
Funding Amount
$505,991.00
Summary
Scientists aim to use our body’s own stem cells to make new nerve cells for brain repair. There are two major types of nerve cell: long range and short range; and until now we did not know how to make new long range nerves. I recently discovered that a special type of brain stem cell, the OPC, makes new long range nerves throughout life. We are building on this discovery by trying to understand the signals that control this process in order to direct OPCs towards nerve regeneration.
Myelin Remodelling: A Novel Form Of Neural Plasticity
Funder
National Health and Medical Research Council
Funding Amount
$605,849.00
Summary
Myelin is the insulation of the central nervous system (CNS). We have demonstrated that CNS insulation is not fixed. It changes throughout life. This project aims to find out why this happens. In particular we will investigate the role of dynamic insulation in learning and memory, and examine the role of nervous system activity in promoting the addition of new insulation. This research will provide valuable insight into multiple sclerosis, Alzheimer's dementia and mental health disorders.
Mapping The Neural Circuits Involved In Appetite And Feeding Behaviour
Funder
National Health and Medical Research Council
Funding Amount
$404,892.00
Summary
My research project involves deconstructing the neural circuitry underlying feeding behaviour using innovative genetically-based methods. I aim to identify and characterise the major projections of the oxytocin-expressing neurons in the paraventricular hypothalamic nucleus, which have recently been identified as critical in the feeding neurocircuitry. This emerging field of research is predicted to transform our understanding and treatment of disorders such as obesity and anorexia nervosa.
Central Nervous System Dendritic Cells – Guilty Or Not Guilty?
Funder
National Health and Medical Research Council
Funding Amount
$481,594.00
Summary
The central nervous system although structurally and functionally unique, must be able to mount protective immunological responses. However, breakdown in local and central immunoregulatory processes can lead to clinically disabling inflammatory conditions such as uveitis and multiple sclerosis. This project will investigate the role of Dendritic cells in models of autoimmune diseases affecting the eye and brain. The data will greatly aid our ability to design new immunotherapies to treat these b ....The central nervous system although structurally and functionally unique, must be able to mount protective immunological responses. However, breakdown in local and central immunoregulatory processes can lead to clinically disabling inflammatory conditions such as uveitis and multiple sclerosis. This project will investigate the role of Dendritic cells in models of autoimmune diseases affecting the eye and brain. The data will greatly aid our ability to design new immunotherapies to treat these blinding and crippling diseases.Read moreRead less
Novel Pathomechanisms And Therapeutic Targets In Neurodegenerative Diseases
Funder
National Health and Medical Research Council
Funding Amount
$340,038.00
Summary
This fellowship will provide new insight into the molecular processes underlying onset and progression of common brain conditions, including Alzheimer’s disease, frontotemporal dementia and motor neuron disease. Furthermore, new therapeutic targets for these diseases will be developed and tested in model systems, to facilitate future translation into clinical application, and to overcome the lack of treatments.
Effects Of Melanocortin Neurons On Systemic Glucose Homeostasis
Funder
National Health and Medical Research Council
Funding Amount
$860,251.00
Summary
There is good evidence that the brain can control blood glucose, but we do not know how this occurs, or why this doesn’t work in diabetes. This grant will use cutting edge mouse genetic technology to determine how the brain controls blood glucose, and what changes in diabetes. This grant will determine how several hormones act through the brain to change glucose levels, and will help develop new strategies to treat high blood glucose.
Site-specific Tau Phosphorylation To Treat And Understand Alzheimer’s Disease
Funder
National Health and Medical Research Council
Funding Amount
$943,902.00
Summary
Alzheimer’s disease (AD) is the most common form of dementia. Unfortunately, current therapies are ineffective. Our laboratory has made an important contribution to understanding the events that lead to brain cell malfunction in AD. I recently found a novel concept that changes the view of AD completely. In the next 3 years, I aim to develop therapeutic tools based on this novel concept and find out more about how it can protect brains from AD.