Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.761166
Title: Investigating the pathogenesis of tau protein in stem cell models of neurodegenerative disease
Author: Wallis, Stephanie
ISNI:       0000 0004 7432 8279
Awarding Body: University of Bristol
Current Institution: University of Bristol
Date of Award: 2018
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Abstract:
Tauopathies are neurodegenerative diseases characterised by the pathological phosphorylation and accumulation of tau protein within the brain. Despite considerable efforts, the molecular pathways underlying tau pathogenesis have not yet been fully elucidated. This has been partially attributed to the limitations of traditionally used in vitro and in vivo models to recapitulate the complex molecular pathways involved in the pathogenesis of tau. The use of human induced pluripotent stem cell (hiPSC) technology has enabled the derivation of disease-relevant cell types from patients with tauopathy. During this project, models of sporadic Alzheimer’s disease (sAD) and frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17) were developed through the derivation of vulnerable neuronal subtypes from hiPSC. Tau-related molecular pathology was assessed in these models and compared to that within human brain tissue to determine the ability of these models to recapitulate the molecular aspects of the disease niche and to inform on the underlying pathways contributing to tau pathogenesis. hiPSC derived from a patient carrying Val337Met MAPT were differentiated to produce cortical glutamatergic neurons (CGNs) to model FTDP-17. This model successfully recapitulated the abnormal tau phosphorylation characteristic of tauopathy and decreased levels of synapsin, indicative of synaptic loss. Additionally, analysis of alterations in the gene expression, protein levels and activity of tau kinases involved in tauopathy recapitulated those seen in the brain, demonstrating the value of this model as a platform for further investigation of the pathogenesis of frontotemporal dementia. Basal forebrain cholinergic neurons (bfCNs) and CGNs, which are vulnerable in sAD, were derived from control human pluripotent stem cell lines and treated with Amyloid-β (Aβ) oligomers for 48 hours to probe the molecular mechanisms underlying Aβ-induced tau pathology. While no evidence of abnormal tau phosphorylation or increased levels of tau were found, the model was found to recapitulate the development of neuronal varicosities and the loss of synapsin. The knowledge gained from this model serves to inform future models employing Aβ oligomer treatment.
Supervisor: Allen-Birt, Shelley Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.761166  DOI: Not available
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