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Updated: Oct 7, 2025
Cell-based Assay to Study Antibody-mediated Tau Clearance by Microglia
Published on: November 9, 2018
p38 Inhibition Decreases Tau Toxicity in Microglia and Improves Their Phagocytic Function
Juan R Perea1,2,3, Marta Bolós1,2, Raquel Cuadros1
1Department of Molecular Neuropathology, Centro de Biología Molecular "Severo Ochoa" (UAM-CSIC), 28049, Madrid, Spain.
Abstract:
Alzheimer's disease (AD) and other tauopathies are histopathologically characterized by tau aggregation, along with a chronic inflammatory response driven by microglia. Over the past few years, the role of microglia in AD has been studied mainly in relation to amyloid-β (Aβ) pathology. Consequently, there is a substantial knowledge gap concerning the molecular mechanisms involved in tau-mediated toxicity and neuroinflammation, thus hindering the development of therapeutic strategies. We previously demonstrated that extracellular soluble tau triggers p38 MAPK activation in microglia. Given the activation of this signaling pathway in AD and its involvement in neuroinflammation processes, here we evaluated the effect of p38 inhibition on primary microglia cultures subjected to tau treatment. Our data showed that the toxic effect driven by tau in microglia was diminished through p38 inhibition. Furthermore, p38 blockade enhanced microglia-mediated tau phagocytosis, as reflected by an increase in the number of lysosomes. In conclusion, these results contribute to our understanding of the functions of p38 in the central nervous system (CNS) beyond tau phosphorylation in neurons and provide further insights into the potential of p38 inhibition as a therapeutic strategy to halt neuroinflammation in tauopathies.
Insights
In Alzheimer's disease (AD) and tauopathies, inhibiting p38 MAPK in microglia reduces tau toxicity. This approach also enhances microglia's ability to clear tau aggregates, offering a potential therapeutic strategy for neuroinflammation.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Alzheimer's disease (AD) and tauopathies feature tau aggregation and microglial neuroinflammation.
- Microglia's role in AD has been primarily linked to amyloid-beta (Aβ) pathology, leaving tau-mediated mechanisms understudied.
- Extracellular soluble tau activates p38 MAPK in microglia, a pathway implicated in neuroinflammation.
Purpose of the Study:
- To investigate the effect of p38 MAPK inhibition on microglia exposed to tau.
- To explore how p38 inhibition influences tau toxicity and clearance by microglia.
Main Methods:
- Primary microglia cultures were treated with tau.
- The impact of p38 MAPK inhibition on tau-treated microglia was assessed.
- Microglia-mediated tau phagocytosis and lysosome activity were quantified.
Main Results:
- Inhibition of p38 MAPK significantly reduced the toxic effects of tau on microglia.
- Blocking p38 MAPK enhanced microglia's phagocytosis of tau.
- Lysosome number increased, indicating improved cellular clearance mechanisms.
Conclusions:
- p38 MAPK plays a crucial role in tau-mediated microglial toxicity and neuroinflammation.
- p38 inhibition presents a promising therapeutic avenue for tauopathies by mitigating neuroinflammation and enhancing tau clearance.
- These findings expand the understanding of p38 MAPK functions in the central nervous system (CNS).
