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Title: Mouse models of tauopathy : cholinergic, inflammatory and glutamatergic phenotyping and effects of pharmacological modification
Author: Cranston, Anna
ISNI:       0000 0004 9353 7295
Awarding Body: University of Aberdeen
Current Institution: University of Aberdeen
Date of Award: 2019
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An early and selective loss of basal forebrain cholinergic neurons is a well-established feature of Alzheimer's disease (AD), alongside disrupted glutamatergic neurotransmission. Intriguingly, tauopathies such as Frontotemporal Lobar Degeneration (FTLD) are lacking such cholinergic degenerations, however both diseases present with robust and age-progressive inflammation throughout the brain. The primary focus of this study was to assess cholinergic, glutamatergic and inflammatory phenotypes within our in-house generated transgenic tau mouse models. Genetically, these models differ by expression of truncated 3-repeat tau fragment in Line 1 (L1), and full-length human tau carrying a double mutation (P301S and G335D) in Line 66 (L66), as models of AD and FTLD, respectively. In L1, a distinct basal forebrain cholinergic loss, alongside moderate microglial activation and attenuated synaptosomal glutamate release was found. This confirms the suitability of L1 as a robust model of AD. In contrast, L66 exhibited robust microglial activation, significantly elevated synaptosomal glutamate release and a relatively intact cholinergic system, factors strongly validating L66 as a suitable model of FTLD. Secondly, the effect of the tau aggregation inhibitor leucomethylthioninium bis(hydromethane sulphonate), known as LMTM, was examined in these mice. This was driven by clinical findings that there was a negative interaction between LMTM and currently approved drugs for AD. LMTM significantly normalised opposing alterations in both synaptosomal glutamate release and glutamatergic and synaptic proteins in L1 and L66, suggesting novel underlying biochemical mechanisms for LMTM. Alterations in synaptosomal glutamate release were additionally identified following combined administration of LMTM with the acetylcholinesterase inhibitor rivastigmine in L1 and L66. In summary, the findings presented here confirms the validity of L1 and L66 as robust pre clinical models of AD and FTLD, and reveals potential molecular targets for LMTM at the synaptic level, findings which contribute significantly to our understanding of the exact underlying mechanisms of this novel compound.
Supervisor: Riedel, Gernot ; Harrington, Charles Sponsor: TauRx Therapeutics Ltd
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Alzheimer's disease ; Phenotype ; Mice ; Nervous system ; Glutamic acid ; Inflammation ; Synaptosomes