Alzheimer’s disease; Microglia; Neuroinflammation; Tau; Tauopathies; p38; Amyloid beta-Peptides; tau Proteins; Amyloid beta-Peptides/metabolism; Humans; Microglia/metabolism; tau Proteins/metabolism; Alzheimer Disease/metabolism; Tauopathies/metabolism; Neuroscience (miscellaneous); Neurology; Cellular and Molecular Neuroscience
Abstract :
[en] 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.
Disciplines :
Neurology
Author, co-author :
Perea, Juan R ; Department of Molecular Neuropathology, Centro de Biología Molecular "Severo Ochoa" (UAM-CSIC), 28049, Madrid, Spain ; Center for Networked Biomedical Research On Neurodegenerative Diseases (CIBERNED), 28031, Madrid, Spain ; German Center for Neurodegenerative Diseases (DZNE), 53127, Bonn, Germany
Bolós, Marta ; Department of Molecular Neuropathology, Centro de Biología Molecular "Severo Ochoa" (UAM-CSIC), 28049, Madrid, Spain ; Center for Networked Biomedical Research On Neurodegenerative Diseases (CIBERNED), 28031, Madrid, Spain
Cuadros, Raquel; Department of Molecular Neuropathology, Centro de Biología Molecular "Severo Ochoa" (UAM-CSIC), 28049, Madrid, Spain
García, Esther; Department of Molecular Neuropathology, Centro de Biología Molecular "Severo Ochoa" (UAM-CSIC), 28049, Madrid, Spain
García-Escudero, Vega ; Department of Molecular Neuropathology, Centro de Biología Molecular "Severo Ochoa" (UAM-CSIC), 28049, Madrid, Spain ; Department of Anatomy, Histology and Neurosciences, Faculty of Medicine, Universidad Autónoma de Madrid (UAM), 28029, Madrid, Spain
Hernández, Félix ; Department of Molecular Neuropathology, Centro de Biología Molecular "Severo Ochoa" (UAM-CSIC), 28049, Madrid, Spain ; Center for Networked Biomedical Research On Neurodegenerative Diseases (CIBERNED), 28031, Madrid, Spain ; Department of Molecular Biology, Faculty of Sciences, Universidad Autónoma de Madrid (UAM), 28049, Madrid, Spain
McManus, Róisín M ; German Center for Neurodegenerative Diseases (DZNE), 53127, Bonn, Germany
HENEKA, Michael ; German Center for Neurodegenerative Diseases (DZNE), 53127, Bonn, Germany
Avila, Jesús ; Department of Molecular Neuropathology, Centro de Biología Molecular "Severo Ochoa" (UAM-CSIC), 28049, Madrid, Spain. javila@cbm.uam.es ; Center for Networked Biomedical Research On Neurodegenerative Diseases (CIBERNED), 28031, Madrid, Spain. javila@cbm.uam.es
External co-authors :
yes
Language :
English
Title :
p38 Inhibition Decreases Tau Toxicity in Microglia and Improves Their Phagocytic Function.
Open Access funding provided thanks to the CRUE-CSIC agreement with Springer Nature. This research was funded by the Spanish Ministry of Science and Innovation (BES-2015–074405, PGC2018-096177-B-I00) and the Center for Networked Biomedical Research on Neurodegenerative Diseases. Institutional grants from the Fundación Ramón Areces and Banco de Santander are also acknowledged. R. M. M. and M. T. H. are supported by the Helmholtz Association, under the project title “Immunology&Inflammation,” project number ZT-0027.
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