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Title: Functional implications of tau-fyn interactions in Alzheimer's disease
Author: Lau, Hay Wun Dawn
ISNI:       0000 0004 5368 4370
Awarding Body: King's College London
Current Institution: King's College London (University of London)
Date of Award: 2015
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Alzheimer’s disease (AD) is characterised by neuropathological deposits of amyloid plaques and neurofibrillary tangles. In AD, tau is abnormally phosphorylated and forms aggregates which spread trans-synaptically throughout the brain. The non-receptor-associated tyrosine kinase fyn is up-regulated in a subset of tangle-bearing neurons in AD brain and fyn also phosphorylates tau. Most tau is axonally located, where it promotes microtubule stability. Both tau and fyn are found in dendrites, where they stabilise receptor complexes at the post-synaptic density. Tau is also trafficked to the plasma membrane in a phosphorylation-dependent process that requires fyn. Tau is also present in the extracellular space, which could play an important role in the spread of tau pathology in AD. The function of tau at the membrane, and the precise role of fyn in tau trafficking are unclear, but they suggest that fyn could contribute to tau propagation. Here, the role of fyn in tau release was investigated in organotypic brain slices. The neurotoxicity of soluble β-amyloid oligomers was examined in organotypic brain slices to investigate their impact on tau release. Interactions between tau and SH2 and SH3 domains of fyn were confirmed. Furthermore, the precise binding site between the proline-rich region of tau and the fyn-SH3 domain was identified. Lentiviruses containing tau mutations that alter the tau-fyn interaction were used to determine the downstream effects in organotypic brain slices. Changes in tau and fyn were investigated in human post-mortem brain tissue from individuals with AD and from unaffected controls. The results presented in this thesis characterise tau-fyn binding and provide insight into the functional implications of this interaction in relation to tau propagation. Understanding the basis of the molecular interactions between tau and fyn will improve our understanding of these important molecular entities and may lead to the discovery of new therapeutic targets for dementia.
Supervisor: Noble, Wendy Jane ; Hanger, Diane Pamela Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available