Sameer Mohammad Khaleel Nazeeruddin
Tauopathies are neurodegenerative diseases whose common pathological feature is the intraneuronal accumulation of tau aggregates. Tau protein has various roles in the neuron, among which stabilization of microtubules (MT), regulation of synaptic activity or axonal transport. Subsequently, tau pathology exerts toxicity through mechanisms that likely involve the loss of normal function or the gain of toxic functions. In tauopathies, tau undergoes post-translational modifications (PTM), which are thought to promote the detachment from the MT, change its subcellular localization, and induce conformational changes that favor its assembly with other tau monomers, forming oligomers and fibrils. Furthermore, both normal and pathological forms of tau can be transferred from neuron to neuron. This process may have an important role in disease progression, by propagating the pathology along synaptically connected brain regions, which reflects the evolution of the symptoms. Therefore, the aggregation of tau protein and its propagation are promising targets for potential treatments. In the present thesis, our objective was to assess the efficacy of two treatments using a mouse model of tauopathy based on local overexpression of the 4R0N human tau (hTau) wild-type (WT) induced by intracerebral injection of an adeno-associated viral (AAV) vector.
In the first part of the thesis, we overexpressed tau in the entorhinal cortex (EC) of WT mice to induce pathology and assess the effects of aggregation inhibitor compounds orally administered. Although we did not observe any effect on markers of tau aggregation, likely because the induced pathology was still at an early stage, the treatment was found to enhance phosphorylation of the Ser202/Thr205 residues in the EC and ipsilateral hippocampus (HPC). Additionally, we measured an increase in the density of microglial cells in the HPC, and significantly decreased levels of total hTau in the cerebrospinal fluid of the treated mice. These findings suggest a potential positive effect of this treatment on the clearance of hTau.
In the second part of the thesis, we unilaterally overexpressed hTau in the mouse CA3 HPC and used the connectivity between both hemispheres to quantify the propagation of tau from neuron-to-neuron to the contralateral HPC. We found neurons labelled for hTau in the contralateral HPC, the number of which was increased in 5xFAD mice carrying the amyloid pathology. Next, to induce an antibody response against pathological tau, we subcutaneously injected a vaccine against the phospho-Ser396/404 tau epitope. The vaccine induced a potent antibody response in WT mice, but antibody titers remained low in the 5xFAD mice. In the treated WT mice, immunohistochemistry showed a decreased PHF-1 immunoreactivity in the HPC, indicating that the generated antibodies indeed recognized the phospho-Ser396/404 epitope. Remarkably, the vaccine decreased the number of neurons positive for hTau in the contralateral HPC, suggesting an effect of immunotherapy on tau propagation. Furthermore, the vaccine also showed potential neuroprotective effects, by decreasing the level of neurodegeneration in the dentate gyrus of treated mice as a function of the anti-phospho-tau antibody titer.
In this work, using adapted AAV8-based models of local tau overexpression in the mouse brain, we reveal the effects of two treatments on different aspects of tau pathology related to the progression of the symptoms in tauopathies.EPFL