Project Details
Description
Dementia is a major health burden and second leading cause of death of Australians. The number of people, living with dementia is expected to increase to approximately 590,000 by 2028, with Alzheimer's disease being the most
prevalent form of dementia. The molecular mechanisms of Alzheimer's disease progression are still poorly understood. A major histopathological hallmark of Alzheimer's disease is the formation of neurofibrillary tangles, made up from hyperphosphorylated forms of the microtubule-associated protein tau. It has been well established that tau pathology progresses throughout the brain tissue of patients with the disease in a common pattern. However, the mechanisms of this spreading at a cellular level are poorly understood. Previous studies provided strong evidence for tau spreading via transsynaptic propagation of tau, which involves multiple cellular factors and pathways. These pathways include the secretion of tau (involving the endosomal and trans-Golgi network) from the
presynaptic compartment of an affected neuron and the uptake of tau (through the endocytic machinery) by a yet healthy neuron. The proposed study aims to develop a spatial and temporal hierarchy of this multi-factorial spreading of tau. For this, we will be using advanced viral gene-transfer technology in combination with cellular assays and mouse models for tau pathology TAU58/2), to dissect the molecular mechanisms of tau spreading via nerve cell connections in the disease. The findings from this study will thereby provide a roadmap for the future characterisation of novel drug targets for slowing or halting the spreading of tau pathology, eventually leading to effective disease treatment and health improvement.
prevalent form of dementia. The molecular mechanisms of Alzheimer's disease progression are still poorly understood. A major histopathological hallmark of Alzheimer's disease is the formation of neurofibrillary tangles, made up from hyperphosphorylated forms of the microtubule-associated protein tau. It has been well established that tau pathology progresses throughout the brain tissue of patients with the disease in a common pattern. However, the mechanisms of this spreading at a cellular level are poorly understood. Previous studies provided strong evidence for tau spreading via transsynaptic propagation of tau, which involves multiple cellular factors and pathways. These pathways include the secretion of tau (involving the endosomal and trans-Golgi network) from the
presynaptic compartment of an affected neuron and the uptake of tau (through the endocytic machinery) by a yet healthy neuron. The proposed study aims to develop a spatial and temporal hierarchy of this multi-factorial spreading of tau. For this, we will be using advanced viral gene-transfer technology in combination with cellular assays and mouse models for tau pathology TAU58/2), to dissect the molecular mechanisms of tau spreading via nerve cell connections in the disease. The findings from this study will thereby provide a roadmap for the future characterisation of novel drug targets for slowing or halting the spreading of tau pathology, eventually leading to effective disease treatment and health improvement.
| Status | Active |
|---|---|
| Effective start/end date | 1/01/21 → 31/12/24 |