• Alzheimer
• nucleus
• regulation of gene expression
• Tau
• transcriptome

Tau is a microtubule (MT) binding protein involved in a large number of dementias known as tauopathies. Canonically, the cytoplasmic role of Tau has been blamed for pathogenesis: hyperphosphorylated Tau detaches from MTs and forms toxic aggregates that engulf the cell cytoplasm and spread to neighbouring cells. However, Tau has roles in various subcellular compartments that might contribute to the onset of dementia and explain early symptoms. In my thesis, I investigated the role of Tau in the nucleus: nuclear Tau is able to modulate the expression of target genes involved in the glutamate pathway, in particular the vesicular glutamate transporter VGluT1, in accordance with the excitotoxicity phenotype. A large number of additional pathways are deregulated, including both neuron-specific features like axon guidance and synaptic potentiation, and systemic outcomes on immunity and glucose metabolism. This widespread deregulation correlates with the relocalization of epigenetic remodellers, suggesting that it might involve the disruption of a silencing complex, to establish an open chromatin state. The resulting transcriptional profile in our cell model of Tau-overexpressing differentiated SH-SY5Y cells is highly consistent with early disease phases in the brain and blood of AD patients. Thus, nuclear Tau might make a significant contribution to the onset of tauopathies.