La sécrétion de la protéine tau : mécanisme de propagation de la pathologie de tau dans la maladie d’Alzheimer
In Alzheimer’s disease, the amyloid plaques and the neurofibrillary tangles composed of misfolded aggregated tau protein are the two hallmarks of the pathology. In the brain, the propagation of tau pathology was observed along the neuronal circuits. Described by Doctor Braak in 1991, the appearence of the neurofibrillary tangles was predictable in the brain and correlated with the degree of cognitive deficits. Its remains unclear how tau pathology spreads in the brain. In our laboratory, we made the hypothesis that the propagation could occur by cell-to-cell transmission. This implies that NFTs would propagate in the brain by the release of misfolded tau aggregates from an affected neuron followed by its uptake in neighboring neurons. My thesis focuses on the mechanism of tau secretion. Firstly, we demonstrated that tau was actively secreted in the extracellular space by non neuronal cells and primary neurons. Then, we characterized the tau secreted forms. Finally, we explored the secretory pathways and the mechanisms leading to tau secretion. We were able to modulate tau secretion by mimicking specific insults observed in Alzheimer disease. Our research led us to identify the Golgi apparatus as a major contributor to tau secretion. Concomitant with this, modulation of cdk5 pathway and rab1A expression, which are known to affect the Golgi morphology, altered significantly tau secretion.   Our research provides new therapeutic strategies for Alzheimer’s disease, targeting tau secretion to reduce the propagation of tau pathology by new cellular mecanisms.
Tau Propagation Alzheimer's disease Secretion Propagation