Prion-like propagation of Tau pathology and heterotypic seeding of Tau by Amyloid-β as key pathogenetic mechanisms in Alzheimer’s disease

Alzheimer’s disease (AD) is the most prevalent form of dementia accounting for up to 70% of all dementia cases, and is pathologically characterized by amyloid plaques and neurofibrillary tangles, respectively composed of amyloid-β peptides and hyperphosphorylated Tau. The amyloid cascade hypothesis is the most prevalent hypothesis in AD, stating that accumulation of Aβ peptides initiates a cascade of events leading to Tau modifications, inflammation and ultimately synaptic and neuronal loss. Combined genetic, pathological, clinical, biomarker data and data from preclinical in vivo models support the amyloid cascade hypothesis and Aβ-induced Tau pathology as one of the major disease mechanisms involved in AD, yet mechanistically poorly understood. Once initiated, the spatiotemporal pattern of Tau pathology in AD strongly correlates with the disease symptoms allowing its use for disease staging. The progression of Tau pathology remains poorly understood, but seems to progress along functional connections, reminiscent of prion-like propagation of protein misfolding. This thesis work focuses on the analysis of molecular mechanisms of spatio-temporal progression of Tau aggregation and its functional repercussions, and mechanisms of Aβ-induced Tau pathology, generally considered key pathogenetic mechanisms in AD.