| Summary: | The tauopathies comprise a broad group of neurodegenerative diseases that are characterised by pathological alterations of tau in the brain that lead to synaptic dysfunction, changes in neuronal bioenergetics and loss of neuronal connectivity. There is growing evidence that tau fragmentation may be at least in part responsible for the clinical presentation in these disorders. In particular, diseases in which four microtubule-binding repeat tau isoforms are overrepresented, such as progressive supranuclear palsy, exhibit a truncated form of wild-type tau (termed Tau35) that is absent from age-matched control brain. However, whether this tau fragment is involved in disease pathogenesis is not yet clear. In the work presented here, potentially pathogenic processes were studied in a new mouse model of tauopathy in which Tau35 is expressed under the control of the human tau promoter. Unlike most existing tau transgenic mice, expression of Tau35 comprises less than 10% of that of endogenous mouse tau and thus is more representative of human tauopathies. Tau35 mice demonstrate key features of human tauopathy, including progressive cognitive and motor deficits and reduced life-span. The work in this thesis has revealed that Tau35 mouse brain exhibits astrocytic activation, autophagosomal accumulation, and a reduction in the number of mitochondria. Investigation of changes in the peripheral nervous system revealed degenerative changes at the neuromuscular junction in aged Tau35 mice. Primary cortical neurons cultured from Tau35 mice demonstrated elevated tau phosphorylation, morphological changes and a significant decrease in the density of dendritic spines. Further analysis of mitochondria in mature Tau35 cortical neurons showed a deficit in mitochondria that was comparable with that found in Tau35 mouse brain, including a reduction in the number of axonal mitochondria. Live-imaging of Tau35 neurons demonstrated altered mitochondrial mobility with a preference towards mitochondrial retrograde movement and reduced anterograde mitochondrial flux. In summary, these findings enhance our understanding of the effects of a particular disease-associated tau fragment on disease progression in the tauopathies. This work provides new insights into potential mechanisms that could represent early events that are adversely affected in the course of human tauopathy. This emulation of disease progression in a novel and highly relevant mouse model of disease will aid discovery of the critical molecular pathways that are affected and may also identify potential therapeutic strategies for human tauopathies.
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