p38 Inhibition Decreases Tau Toxicity in Microglia and Improves Their Phagocytic Function

被引:14
|
作者
Perea, Juan R. [1 ,2 ,3 ]
Bolos, Marta [1 ,2 ]
Cuadros, Raquel [1 ]
Garcia, Esther [1 ]
Garcia-Escudero, Vega [1 ,4 ]
Hernandez, Felix [1 ,2 ,5 ]
McManus, Roisin M. [3 ]
Heneka, Michael T. [3 ]
Avila, Jesus [1 ,2 ]
机构
[1] Ctr Biol Mol Severo Ochoa UAM CSIC, Dept Mol Neuropathol, Madrid 28049, Spain
[2] Ctr Networked Biomed Res Neurodegenerat Dis CIBER, Madrid 28031, Spain
[3] German Ctr Neurodegenerat Dis DZNE, D-53127 Bonn, Germany
[4] Univ Autonoma Madrid UAM, Fac Med, Dept Anat Histol & Neurosci, Madrid 28029, Spain
[5] Univ Autonoma Madrid UAM, Fac Sci, Dept Mol Biol, Madrid 28049, Spain
关键词
Tau; p38; Microglia; Tauopathies; Alzheimer's disease; Neuroinflammation; PAIRED HELICAL FILAMENTS; PROTEIN-TAU; EXTRACELLULAR TAU; ALZHEIMER-DISEASE; TRANSGENIC MICE; MOUSE MODEL; IN-VITRO; PHOSPHORYLATION; KINASE; PROMOTES;
D O I
10.1007/s12035-021-02715-0
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
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-beta (A beta) 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.
引用
收藏
页码:1632 / 1648
页数:17
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