Efecto de tau en la respuesta inflamatoria de la microglía

Resum

Microglia are the cells that comprise the innate immune system in the brain. Since their description more than a century ago, they have had a secondary role in the central nervous system (CNS) with respect to the main character, neurons. However, the latest advances have revealed its complexity and importance in some neurodegenerative diseases such as Alzheimer's disease (AD), the most common form of dementia associated with aging. This pathology is characterized by the accumulation of amyloid-β peptide (Aβ) that shapes senile plaques, as well as by the aggregation of hyperphosphorylated tau protein leading to neurofibrillary tangle (NFT) formation. Over the past few years, efforts have been focused on studying the interaction between Aβ and microglia, together with the ability of these cells to decrease the levels of this peptide. Given that most clinical trials based on this strategy have failed, current advances are based on deciphering the molecular mechanisms that triggers the inflammatory response of the microglia driven by tau. In this work, it has been possible to confirm that CX3CR1, a specific microglial receptor, is involved in tau phagocytosis by these cells. Thus, absence of CX3CR1 causes a lower internalisation of tau and, consequently, a reduction in its cytotoxicity. On the other hand, this study demonstrated that non-phosphorylated tau induces the activation of p38 MAPK pathway independently of CX3CR1 and its internalisation. For this reason, tau could be activating this route through any other receptor. As a result, p38 boosts a proinflammatory profile that leads to microglial death. Despite p38 inhibition impaired microglial migration, its effect attenuated cytokines secretion and apoptosis, and tau phagocytosis by these cells was increased. Finally, two mice models (C57BL/6J injected with Tau-Cy5 or P301S) were used in order to analyse p38 activation in vivo. While previous studies attributed this activation to neurons and their role in tau phosphorylation, it has been demonstrated that most of p38 activation was restricted to microglia. In conclusion, this thesis highlights the importance of non-phosphorylated monomeric forms of tau, to the detriment of hyperphosphorylated ones, in the inflammatory response of microglia driven by p38 MAPK pathway. Therefore, p38 inhibition could represent a promising therapeutic strategy to halt neuroinflammation that takes place in tauopathies