Caratterizzazione della proteina Tau in modelli murini di malattie da prioni

Taupathies represent a heterogeneous group of neurodegenerative disorders, characterised by a conformational change in tau, a cytoskeleton-associated protein, in its pathological hyperphosphorylated and aggregated isoform, which is supposed to be involved in cell death processes. In addition to phosphorylation, other post-translational modifications, including acetylation, are believed to promote pathological tau formation. Recently, brain accumulations of hyperphosphorylated tau have been shown in various forms of prion diseases. Not much is known about the role of tau in these diseases, but the accumulation of neurotoxic tau isoforms is presumed to contribute to the broad phenotypic heterogeneity that characterises different prion diseases. The Laboratory of Prion Neurobiology at the Mario Negri Institute for Pharmacological Research, where I conducted my thesis training, has developed three transgenic mouse models that express mutated prion proteins (PrP) and reproduce key clinical and neuropathological features of the three main forms of genetic prion diseases: GSS, CJD and FFI. The aim of my thesis was to verify the presence of pathological isoforms of tau in these models. In biochemical analysis, we observed an increasing trend in the insoluble fraction of tau and some of its phosphorylated isoforms in the brains of transgenic mice compared to wild-type controls, but no change in acetylated tau levels. Immunohistochemical analysis with antibodies directed against certain phosphorylated forms of tau showed deposits of tau in different brain areas and an increase in the number and mean size of the cells that were positive for phosphorylated tau in transgenic mice expressing mutated PrP compared to wild-type controls. In conclusion, the results of my experimental work indicate an increase in phosphorylated and non-phosphorylated tau levels in different prion disease models, paving the way for further investigations to clarify whether there are specific differences between the different models that may contribute to the phenotypic variability of genetic prion diseases.