Abstract
Tauopathies are a group of neurodegenerative diseases characterized by the accumulation of hyperphosphorylated tau protein in the brain. Many of these pathologies also present an inflammatory component determined by the activation of microglia, the resident immune cells of the brain. p38 MAPK is one of the molecular pathways involved in neuroinflammation. Although this kinase is expressed mainly in glia, its activation in certain neurodegenerative diseases such as Alzheimer's Disease has been associated with its ability to phosphorylate tau in neurons. Using the P301S Tauopathy mouse model, here we show that p38 activation increases during aging and that this occurs mainly in microglia of the hippocampus rather than in neurons. Furthermore, we have observed that these mice present an activated microglial variant called rod microglia. Interestingly, p38 activation in this subpopulation of microglia is decreased. On the basis of our findings, we propose that rod microglia might have a neuroprotective phenotype in the context of tau pathology.
Highlights
Tau is a microtubule-associated protein that regulates microtubule assembly and stabilization[1]
In recent years, research into its role in the central nervous system (CNS) has been focused on tau phosphorylation in n eurons[56,57,58], overlooking additional functions in other cell types
We reported that p38 activation increased with age in the hippocampus, and this activation occurred mainly in microglia
Summary
Of pp38+GFAP+ cells was extensive (Fig. 2H). This result could be related to the fact that extracellular tau was able to induce p38 activation in primary cultures of astrocytes (Supplementary Fig. S2 online). Western blot analysis showed that p38 activation occurred predominantly in the hippocampus (Fig. 1A-B) To solve this discrepancy, we quantified pp[38] intensity as a measure of p38 activity in each cell population individually in 12-month-old mice, showing that p38 was found to be strongly activated in microglia rather than in neurons or astrocytes (Fig. 4A). The analysis of pp[38] intensity in N euN+ cells showed that p38 activation was increased (t = 2.881; p < 0.0001) in the neurons of the hippocampus of P301S mice compared to WT (Fig. 4) These data further confirmed the results obtained by western blot (Fig. 1A-B) and were related to the increase in tau phosphorylation (AT8 and PHF-1) in the hippocampal region (Supplementary Fig. S1 online). Taking into account that p38 activation is related to inflammatory processes[36], rod microglia might have a less activated phenotype
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