Abstract
Human neurodegenerative tauopathies exhibit pathological tau aggregates in the brain along with diverse clinical features including cognitive and motor dysfunction. Post-translational modifications of tau, including tau phosphorylation and truncation, are characteristic features of human tauopathy. We previously identified a highly phosphorylated and truncated form of tau associated with the development of disease in humans. We have generated a new mouse model of tauopathy in which this human brain-derived, tau fragment (Tau35) is expressed under the control of the human tau promoter. Notably, unlike most existing mouse models of tauopathy, the Tau35 transgene encoding truncated wild-type tau, is expressed at less than 10% of the amount of endogenous mouse tau.Behavioural and phenotypic assessments showed that Tau35 mice exhibit a disease-associated phenotype of reduced survival, clasping, kyphosis and defective motor function. Cognitive testing in the Morris water maze also revealed a deficit in spatial learning and hippocampal dependent memory. Neuropathological examination using a range of antibodies to tau, including phosphorylated and conformational epitopes, showed a progressive accumulation of aggregated and phosphorylated tau inclusions, comprising both endogenous and transgenically expressed tau. Alterations in several disease-associated proteins were also detected in Tau35 mice, including kinase activity, and proteins involved in autophagic-lysosomal and synaptic function, suggesting a toxic gain of function of this tau fragment. Importantly, we found that a pharmacological agent reverses the molecular and behavioural neurodegenerative phenotype apparent in Tau35 mice. Backcrossing the original mixed background Tau35 mice onto a pure C57BL/6 background revealed that the previously observed behavioural deficits were preserved in this mouse model. A novel cell based CHO-Tau35 phosphorylation assay was successfully established in which to test potential therapeutic compounds.
These results show for the first time that minimal expression of a wild-type human disease-associated tau fragment in Tau35 mice causes a profound and progressive tauopathy, which can be rescued by pharmacological intervention. Tau35 mice therefore represent a highly disease-relevant animal model in which to investigate molecular mechanisms underlying tau-associated neurodegeneration and to develop novel and innovative therapies for human tauopathies.
| Date of Award | 2016 |
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| Original language | English |
| Awarding Institution |
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| Supervisor | Diane Hanger (Supervisor) & Wendy Noble (Supervisor) |