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[{"model": "core.projectfund", "pk": 30789, "fields": {"project": 8015, "organisation": 49, "amount": 0, "start_date": "2021-09-26", "end_date": "2025-09-29", "raw_data": 42406}}]
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[{"model": "core.projectorganisation", "pk": 87780, "fields": {"project": 8015, "organisation": 1998, "role": "LEAD_ORG"}}]
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[{"model": "core.projectperson", "pk": 54853, "fields": {"project": 8015, "person": 11068, "role": "STUDENT_PER"}}]
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[{"model": "core.projectperson", "pk": 54852, "fields": {"project": 8015, "person": 11069, "role": "SUPER_PER"}}]
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{"title": ["", "An investigation of the bidirectional relationship between tau protein propagation and neural circuit activity in mouse models of Alzheimer's disease"], "description": ["", "\nAlzheimer's disease (AD) is a debilitating neurodegenerative disorder that is defined by the presence\nof extracellular amyloid-beta plaques and intracellular tau-protein-containing neurofibrillary tangles in\nthe brain1. There are currently no effective treatments available and removing amyloid-beta has thus far\nbeen ineffective in clinical trials. As such, my project will focus on tau pathology and its mechanisms\nat the neural circuit level, with a view to elucidating the role of tau in pathoprogression of AD and\ninforming future circuit-level therapeutic approaches.\nTau pathology in humans involves propagation of tau beginning in the entorhinal cortex, spreading to\nthe hippocampus, then the cerebral cortex2, and this propagation parallels the clinical stages of the\ndisease. However, the mechanism(s) linking protein accumulation and cognitive decline is unknown.\nNeuronal hyperexcitability precedes tau propagation and accumulation in disease models, and there\nis evidence that neuronal activity enhances tau propagation and pathology in vivo3, although the\nmechanism for this is not established. Furthermore, there is evidence for tau-dependent suppression\nof activity and silencing of neurons4, with cell-type specific selective vulnerability5,6.\nThe aim of this project will be to study neuronal dysfunction in the context of tau at the circuit level,\nemploying complimentary large-scale electrophysiological (Neuropixels), two- and one-photon\ncalcium and voltage imaging, and behavioural studies to answer two key questions:\nHow does activity in neural circuits affect tau propagation?\nHow does tau propagation affect activity in neural circuits, and thereby cognition?\nIn addressing these questions, I will investigate mechanisms for the interaction between tau and\nneural activity in multiple Alzheimer's disease mouse models, which will advance our understanding\nof the disease pathogenesis, and have relevance for therapeutic approaches based on modulating\nexcitability, potentially in a cell-type specific manner.\nBibliography:\n1. Knopman, D. S. et al. Alzheimer disease. Nat. Rev. Dis. Primer 7, 1-21 (2021).\n2. Busche, M. A. & Hyman, B. T. Synergy between amyloid-beta and tau in Alzheimer's disease. Nat.\nNeurosci. 23, 1183-1193 (2020).\n3. Wu, J. W. et al. Neuronal activity enhances tau propagation and tau pathology in vivo. Nat.\nNeurosci. 19, 1085-1092 (2016).\n4. Busche, M. A. et al. Tau impairs neural circuits, dominating amyloid-beta effects, in Alzheimer\nmodels in vivo. Nat. Neurosci. 22, 57-64 (2019).\n5. Turkes, E. & Duff, K. E. Cell-type specific selective vulnerability to pathological tau in Alzheimer's\ndisease. Alzheimers Dement. 16, e043149 (2020).\n6. Fu, H. et al. A tau homeostasis signature is linked with the cellular and regional vulnerability of\nexcitatory neurons to tau pathology. Nat. Neurosci. 22, 47-56 (2019).\n\n"], "extra_text": ["", "\n\n\n\n"], "status": ["", "Active"]}
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| Jan. 28, 2023, 10:51 a.m. |
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{"external_links": [32935]}
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| Jan. 28, 2023, 10:51 a.m. |
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[{"model": "core.project", "pk": 8015, "fields": {"owner": null, "is_locked": false, "coped_id": "46626f70-666e-42bc-8e45-80101c282c57", "title": "", "description": "", "extra_text": "", "status": "", "start": null, "end": null, "raw_data": 42390, "created": "2023-01-28T10:35:52.846Z", "modified": "2023-01-28T10:35:52.846Z", "external_links": []}}]
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