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Title: Metabolic and cellular phenotypes in a PLB mouse model of dementia
Author: Hull, Claire
ISNI:       0000 0004 7967 6977
Awarding Body: University of Aberdeen
Current Institution: University of Aberdeen
Date of Award: 2019
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Type 2 diabetes mellitus (T2D) and dementia are two of the most predominant conditions in the elderly. To date, there is increasing evidence supporting a link between metabolic dysfunction and neurodegenerative diseases such as Alzheimer's disease (AD) and frontotemporal dementia (FTD). Hyperglycaemia, insulin resistance and glucose intolerance are recognised risk factors of dementia with considerable evidence emerging from epidemiological and experimental studies suggesting possible shared molecular and cellular pathways linking these two disorders. However, the precise mechanisms underlying this association remains unknown. The present thesis focused on investigating the role of the microtubule-associated protein tau as a potential link between FTD and alterations in metabolic signalling, using a mouse model of neuronal specific human mutated Tau (R301L; R406W) knock-in, termed PLB2TAU. Interestingly, PLB2TAU mice display FTD-like phenotypes, however, they were also found to display T2D-like symptoms. PLB2TAU mice therefore provide a useful tool for investigating the underlying links between FTD and T2D with the aim of finding efficient treatments. In addition to this, the impact of high fat diet (HFD) on FTD-related pathologies in PLBTAU mice was investigated. It was established that mutated htau is sufficient to drive phosphorylated tau pathology alongside neuroinflammation and impaired cellular protein handling, but also produce changes in metabolic signalling in both the brain and peripheral tissues of PLB2TAU mice. Following this, HFD was determined to cause HFD-induced obesity and associated alterations in ER stress through activation of insulin signalling markers, resulting in the accumulation of insoluble hyperphosphorylated tau aggregates. Finally, the effects of MCC950 (NLRP3 inhibitor) were investigated in PLB2TAU mice. MCC950 treatment resulted in a number of beneficial effects such as increased insulin sensitivity, reversal of insulin resistance and reduced inflammation. Overall, this project has uncovered a number of signalling pathways and mechanisms that suggest abnormal tau function may be an important regulator of metabolic function and may now allow more targeted drug discovery.
Supervisor: Platt, Bettina ; Riedel, Gernot Sponsor: Alzheimer's Society
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Dementia ; Mice ; Proteins ; Phenotype ; Diabetes ; Insulin ; Glucose