Investigation of tau pathology in a P301S tau transgenic mouse model of Frontotemporal dementia
thesisposted on 2022-03-28, 18:44 authored by Magdalena Przybyla
Alzheimer´s disease (AD) and frontotemporal dementia (FTD) are two of the most prevalent causes of dementia. Both neurodegenerative disorders are characterized by intracellular neurofibrillary tangles (NFT), composed of hyperphosphorylated protein tau (Gotz and Ittner, 2008, Arendt et al., 2016). Under physiological conditions, tau promotes and regulates microtubule dynamics, which emphasizes the important role of tau in the development, maintenance and function of neurons and its contribution to neuronal viability (Bunker et al., 2006). However, in the pathogenesis of neurodegenerative disorders tau is abnormally phosphorylated, dissociates from microtubules and may thereby contribute to microtubule breakdown and axonal transport dysfunction. Following this, tau undergoes secondary modifications and accumulates into insoluble NFTs. With the identification of FTD mutations in the gene encoding tau, MAPT, a direct linkage between tau gene mutations and neurodegenerative disorders was established and further emphasized that tau dysfunction per se is sufficient to cause neurodegeneration and cognitive decline. Since then, transgenic mice carrying pathogenic MAPT mutations have been generated which have provided new insights into the pathomechanistic role of tau in disease and have significantly contributed to the understanding of mechanisms underlying the pathophysiology of AD and related tauopathies. Recently, we characterized a novel tau transgenic mouse line, known as TAU58/2. These mice express the human tau P301S mutation under the control of the Thy1.2 promoter, which in mice restricts the transgene expression to neurons. The TAU58/2 transgenic mice recapitulate essential features of AD, FTD and related tauopathies, including the presence of hyperphosphorylated human tau, abundant NFT formation throughout the brain and spinal cord and neuronal spheroid formation, prior to tau deposition. In addition, histopathological markers were accompanied by an early onset of progressive motor deficits, including a decline in motor strength, balance and coordination. However, our original study primarily focused on the motor deficits of the TAU58/2 and did not determine whether expression of P301S mutant human tau also affected other functional outcomes. Therefore, this thesis aims to determine the role of P301S mutant human tau in the development of behavioural, functional and cognitive deficits in the TAU58/2 transgenic mouse line. The first part of this thesis focusses on the question of whether the expression of P301S mutant human tau impacts on other aspects of behaviour, aside from motor impairments. Here, I determined that TAU58/2 mice develop progressive and early onset disinhibition-like behaviour and increased motor activity when subjected to the elevated plus maze (EPM) and the Open field apparatus, respectively. Further, I determined that these behavioural changes are accompanied by early and progressive tau deposition in the amygdala. Interestingly, significant tau pathology and atrophy of the amygdala has been observed in early stages of FTD and related tauopathies. Considering the importance of the amygdala in controlling behaviour, early onset of pathology and behavioural changes in the EPM in TAU58/2 mice suggests a contributing role to the clinical presentation of FTD. The second part of this thesis characterizes the effects of transgenic P301S mutant human tau expression on neuronal network function in the murine hippocampus. Here, I found that the onset of progressive spatial learning deficits in TAU58/2 transgenic mice were paralleled by deficits in long-term potentiation (LTP) and neuronal network aberrations using electrophysiological and electroencephalography (EEG) recordings, respectively. Further, gene-expression profiling at onset of deficits in TAU58/2 mice revealed a signature of immediate early genes (IEG) that is consistent with neuronal network hypersynchronicity. Finally, I determined that increased IEG activity was confined to neurons harboring tau pathology, providing a cellular link between aberrant tau and network dysfunction. Taken together, our data suggests that tau pathology drives neuronal network dysfunction through hyperexcitation of individual, pathology-harboring neurons as a major contributor to memory deficits. Both studies provide new insights into the pathomechanistic role of tau in disease and may thereby assist in the identification of new targets for future translation into therapy.