Joel, Z; (2015) Primary characterisation of a novel mouse model of tauopathy. Doctoral thesis , UCL (University College London).

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Abstract

The protein tau has gained notoriety due its role in many neurodegenerative disorders including the most prevalent form of dementia, Alzheimer’s disease, as well as the hereditary frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP- 17). The development of novel systems for investigating tau-mediated dysfunction and possible ways in which this may be reversed or even prevented are therefore essential. The present study provides primary characterisation of a novel transgenic mouse model of tauopathy, known as TauD35. This model harbours transgenic human tau containing the FTDP-17 mutation, P301L, under the control of the CaMKIIα promoter. As demonstrated in Alzheimer’s disease, hippocampal neurones are particularly vulnerable to tau dysfunction, fuelling the decision to choose the hippocampus as the site of this initial characterisation. Molecular biology, immunohistochemistry, behavioural and electrophysiological techniques were employed at 4, 13 and 24 months of age in order to investigate pathology development over time. Investigations revealed two sublines within the TauD35 model, with one line harbouring approximately double the number of transgene copies (HIGHTAU) compared to the other (LOWTAU). Both transgenic lines developed intraneuronal inclusions formed from pathological tau species relevant to human tauopathies in an age- and dose-dependent manner, as tested with specific antibodies. At 4-months, prior to tau aggregation, an increase in paired-pulse ratio was detected at entorhinal cortex to dentate gyrus synapses. At 13-months, the two lines exhibited large disparity in NFT load, with HIGHTAU animals displaying behavioural changes consistent with the symptoms of FTDP-17 patients. Neuronal loss was evident in the CA1 region of HIGHTAU mice by 17.5 months of age, coinciding with the development of a pathological phenotype. These data show that both TauD35 models mimic cardinal features of human tauopathies, and thus provide valuable tools in which to study tau dysfunction as well as assess possible therapeutics.

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