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
Résumé :
[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 :
Neurologie
Auteur, co-auteur :
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
Co-auteurs externes :
yes
Langue du document :
Anglais
Titre :
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.
Wimo A, Guerchet M, Ali G-C et al (2017) The worldwide costs of dementia 2015 and comparisons with 2010. Alzheimers Dement 13:1–7. 10.1016/j.jalz.2016.07.150 DOI: 10.1016/j.jalz.2016.07.150
GBD (2016) Dementia Collaborators (2019) Global, regional, and national burden of Alzheimer’s disease and other dementias, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol 18:88–106. 10.1016/S1474-4422(18)30403-4 DOI: 10.1016/S1474-4422(18)30403-4
Masters CL, Simms G, Weinman NA et al (1985) Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proc Natl Acad Sci USA 82:4245–4249. 10.1073/pnas.82.12.4245 DOI: 10.1073/pnas.82.12.4245
Jarrett JT, Berger EP, Lansbury PT (1993) The C-terminus of the beta protein is critical in amyloidogenesis. Ann N Y Acad Sci 695:144–148. 10.1111/j.1749-6632.1993.tb23043.x DOI: 10.1111/j.1749-6632.1993.tb23043.x
Maggio JE, Stimson ER, Ghilardi JR et al (1992) Reversible in vitro growth of Alzheimer disease beta-amyloid plaques by deposition of labeled amyloid peptide. Proc Natl Acad Sci USA 89:5462–5466. 10.1073/pnas.89.12.5462 DOI: 10.1073/pnas.89.12.5462
Kidd M (1963) Paired helical filaments in electron microscopy of Alzheimer’s disease. Nature 197:192–193. 10.1038/197192b0 DOI: 10.1038/197192b0
Crowther RA, Wischik CM (1985) Image reconstruction of the Alzheimer paired helical filament. EMBO J 4:3661–3665. 10.1002/j.1460-2075.1985.tb04132.x DOI: 10.1002/j.1460-2075.1985.tb04132.x
von Bergen M, Friedhoff P, Biernat J et al (2000) Assembly of tau protein into Alzheimer paired helical filaments depends on a local sequence motif ((306)VQIVYK(311)) forming beta structure. Proc Natl Acad Sci USA 97:5129–5134. 10.1073/pnas.97.10.5129 DOI: 10.1073/pnas.97.10.5129
Serrano-Pozo A, Frosch MP, Masliah E, Hyman BT (2011) Neuropathological alterations in Alzheimer disease. Cold Spring Harb Perspect Med 1:a006189. 10.1101/cshperspect.a006189 DOI: 10.1101/cshperspect.a006189
Weingarten MD, Lockwood AH, Hwo SY, Kirschner MW (1975) A protein factor essential for microtubule assembly. Proc Natl Acad Sci USA 72:1858–1862. 10.1073/pnas.72.5.1858 DOI: 10.1073/pnas.72.5.1858
Dixit R, Ross JL, Goldman YE, Holzbaur ELF (2008) Differential regulation of dynein and kinesin motor proteins by tau. Science 319:1086–1089. 10.1126/science.1152993 DOI: 10.1126/science.1152993
Perea JR, Bolós M, Avila J (2020) Microglia in Alzheimer’s disease in the context of tau pathology. Biomolecules 10:1439. 10.3390/biom10101439 DOI: 10.3390/biom10101439
Tapia-Rojas C, Cabezas-Opazo F, Deaton CA et al (2019) It’s all about tau. Prog Neurobiol 175:54–76. 10.1016/j.pneurobio.2018.12.005 DOI: 10.1016/j.pneurobio.2018.12.005
Rösler TW, Tayaranian Marvian A, Brendel M et al (2019) Four-repeat tauopathies. Prog Neurobiol 180:101644. 10.1016/j.pneurobio.2019.101644 DOI: 10.1016/j.pneurobio.2019.101644
Grundke-Iqbal I, Iqbal K, Tung YC et al (1986) Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology. Proc Natl Acad Sci U S A 83:4913–4917. 10.1073/pnas.83.13.4913 DOI: 10.1073/pnas.83.13.4913
Biernat J, Gustke N, Drewes G et al (1993) Phosphorylation of Ser262 strongly reduces binding of tau to microtubules: distinction between PHF-like immunoreactivity and microtubule binding. Neuron 11:153–163. 10.1016/0896-6273(93)90279-z DOI: 10.1016/0896-6273(93)90279-z
Bondareff W, Mountjoy CQ, Roth M, Hauser DL (1989) Neurofibrillary degeneration and neuronal loss in Alzheimer’s disease. Neurobiol Aging 10:709–715. 10.1016/0197-4580(89)90007-9 DOI: 10.1016/0197-4580(89)90007-9
Morsch R, Simon W, Coleman PD (1999) Neurons may live for decades with neurofibrillary tangles. J Neuropathol Exp Neurol 58:188–197. 10.1097/00005072-199902000-00008 DOI: 10.1097/00005072-199902000-00008
Kuchibhotla KV, Wegmann S, Kopeikina KJ et al (2014) Neurofibrillary tangle-bearing neurons are functionally integrated in cortical circuits in vivo. Proc Natl Acad Sci USA 111:510–514. 10.1073/pnas.1318807111 DOI: 10.1073/pnas.1318807111
Andorfer C, Acker CM, Kress Y et al (2005) Cell-cycle reentry and cell death in transgenic mice expressing nonmutant human tau isoforms. J Neurosci 25:5446–5454. 10.1523/JNEUROSCI.4637-04.2005 DOI: 10.1523/JNEUROSCI.4637-04.2005
Santacruz K, Lewis J, Spires T et al (2005) Tau suppression in a neurodegenerative mouse model improves memory function. Science 309:476–481. 10.1126/science.1113694 DOI: 10.1126/science.1113694
Sydow A, Van der Jeugd A, Zheng F et al (2011) Tau-induced defects in synaptic plasticity, learning, and memory are reversible in transgenic mice after switching off the toxic Tau mutant. J Neurosci 31:2511–2525. 10.1523/JNEUROSCI.5245-10.2011 DOI: 10.1523/JNEUROSCI.5245-10.2011
Van der Jeugd A, Hochgräfe K, Ahmed T et al (2012) Cognitive defects are reversible in inducible mice expressing pro-aggregant full-length human Tau. Acta Neuropathol 123:787–805. 10.1007/s00401-012-0987-3 DOI: 10.1007/s00401-012-0987-3
Cowan CM, Mudher A (2013) Are tau aggregates toxic or protective in tauopathies? Front Neurol 4:114. 10.3389/fneur.2013.00114 DOI: 10.3389/fneur.2013.00114
Bengoa-Vergniory N, Velentza-Almpani E, Silva AM et al (2021) Tau-proximity ligation assay reveals extensive previously undetected pathology prior to neurofibrillary tangles in preclinical Alzheimer’s disease. Acta Neuropathol Commun 9:1–20. 10.1186/s40478-020-01117-y DOI: 10.1186/s40478-020-01117-y
Wu JW, Herman M, Liu L et al (2013) Small misfolded tau species are internalized via bulk endocytosis and anterogradely and retrogradely transported in neurons. J Biol Chem 288:1856–1870. 10.1074/jbc.M112.394528 DOI: 10.1074/jbc.M112.394528
Gómez-Ramos A, Díaz-Hernández M, Rubio A et al (2008) Extracellular tau promotes intracellular calcium increase through M1 and M3 muscarinic receptors in neuronal cells. Mol Cell Neurosci 37:673–681. 10.1016/j.mcn.2007.12.010 DOI: 10.1016/j.mcn.2007.12.010
Holmes BB, DeVos SL, Kfoury N et al (2013) Heparan sulfate proteoglycans mediate internalization and propagation of specific proteopathic seeds. Proc Natl Acad Sci USA 110:E3138–E3147. 10.1073/pnas.1301440110 DOI: 10.1073/pnas.1301440110
Calafate S, Flavin W, Verstreken P, Moechars D (2016) Loss of Bin1 promotes the propagation of tau pathology. Cell Rep 17:931–940. 10.1016/j.celrep.2016.09.063 DOI: 10.1016/j.celrep.2016.09.063
Martini-Stoica H, Cole AL, Swartzlander DB et al (2018) TFEB enhances astroglial uptake of extracellular tau species and reduces tau spreading. J Exp Med 215:2355–2377. 10.1084/jem.20172158 DOI: 10.1084/jem.20172158
Perea JR, López E, Díez-Ballesteros JC et al (2019) Extracellular monomeric tau is internalized by astrocytes. Front Neurosci 13:442. 10.3389/fnins.2019.00442 DOI: 10.3389/fnins.2019.00442
Luo W, Liu W, Hu X et al (2015) Microglial internalization and degradation of pathological tau is enhanced by an anti-tau monoclonal antibody. Sci Rep 5:11161. 10.1038/srep11161 DOI: 10.1038/srep11161
Bolós M, Llorens-Martín M, Jurado-Arjona J et al (2015) Direct evidence of internalization of tau by microglia in vitro and in vivo. J Alzheimers Dis 50:77–87. 10.3233/JAD-150704 DOI: 10.3233/JAD-150704
Alliot F, Godin I, Pessac B (1999) Microglia derive from progenitors, originating from the yolk sac, and which proliferate in the brain. Brain Res Dev Brain Res 117:145–152. 10.1016/s0165-3806(99)00113-3 DOI: 10.1016/s0165-3806(99)00113-3
Ginhoux F, Greter M, Leboeuf M et al (2010) Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330:841–845. 10.1126/science.1194637 DOI: 10.1126/science.1194637
Lawson LJ, Perry VH, Dri P, Gordon S (1990) Heterogeneity in the distribution and morphology of microglia in the normal adult mouse brain. Neuroscience 39:151–170. 10.1016/0306-4522(90)90229-w DOI: 10.1016/0306-4522(90)90229-w
Alzheimer A (1910) Beiträge zur Kenntnis der pathologischen Neuroglia und ihrer Beziehungen zu den Abbauvorgängen im Nervengewebe. In: Histologische und histopathologische Arbeiten über die Grosshirnrinde mit besonderer Berücksichtigung der pathologischen Anatomie der Geisteskrankheiten. Gustav Fischer, Jena, pp 401–562
Cras P, Kawai M, Siedlak S, Perry G (1991) Microglia are associated with the extracellular neurofibrillary tangles of Alzheimer disease. Brain Res 558:312–314. 10.1016/0006-8993(91)90783-r DOI: 10.1016/0006-8993(91)90783-r
El Khoury J, Hickman SE, Thomas CA et al (1996) Scavenger receptor-mediated adhesion of microglia to beta-amyloid fibrils. Nature 382:716–719. 10.1038/382716a0 DOI: 10.1038/382716a0
Ising C, Venegas C, Zhang S et al (2019) NLRP3 inflammasome activation drives tau pathology. Nature 575:669–673. 10.1038/s41586-019-1769-z DOI: 10.1038/s41586-019-1769-z
Perea JR, Ávila J, Bolós M (2018) Dephosphorylated rather than hyperphosphorylated tau triggers a pro-inflammatory profile in microglia through the p38 MAPK pathway. Exp Neurol 310:14–21. 10.1016/j.expneurol.2018.08.007 DOI: 10.1016/j.expneurol.2018.08.007
Kyriakis JM, Avruch J (2012) Mammalian MAPK signal transduction pathways activated by stress and inflammation: a 10-year update. Physiol Rev 92:689–737. 10.1152/physrev.00028.2011 DOI: 10.1152/physrev.00028.2011
Canovas B, Nebreda AR (2021) Diversity and versatility of p38 kinase signalling in health and disease. Nat Rev Mol Cell Biol 22:346–366. 10.1038/s41580-020-00322-w DOI: 10.1038/s41580-020-00322-w
Bachstetter AD, Van Eldik LJ (2010) The p38 MAP kinase family as regulators of proinflammatory cytokine production in degenerative diseases of the CNS. Aging Dis 1:199–211
Hensley K, Floyd RA, Zheng NY et al (1999) p38 kinase is activated in the Alzheimer’s disease brain. J Neurochem 72:2053–2058. 10.1046/j.1471-4159.1999.0722053.x DOI: 10.1046/j.1471-4159.1999.0722053.x
Goedert M, Hasegawa M, Jakes R et al (1997) Phosphorylation of microtubule-associated protein tau by stress-activated protein kinases. FEBS Lett 409:57–62. 10.1016/s0014-5793(97)00483-3 DOI: 10.1016/s0014-5793(97)00483-3
Reynolds CH, Nebreda AR, Gibb GM et al (1997) Reactivating kinase/p38 phosphorylates tau protein in vitro. J Neurochem 69:191–198. 10.1046/j.1471-4159.1997.69010191.x DOI: 10.1046/j.1471-4159.1997.69010191.x
Reynolds CH, Betts JC, Blackstock WP et al (2000) Phosphorylation sites on tau identified by nanoelectrospray mass spectrometry: differences in vitro between the mitogen-activated protein kinases ERK2, c-Jun N-terminal kinase and P38, and glycogen synthase kinase-3beta. J Neurochem 74:1587–1595. 10.1046/j.1471-4159.2000.0741587.x DOI: 10.1046/j.1471-4159.2000.0741587.x
Feijoo C, Campbell DG, Jakes R et al (2005) Evidence that phosphorylation of the microtubule-associated protein Tau by SAPK4/p38delta at Thr50 promotes microtubule assembly. J Cell Sci 118:397–408. 10.1242/jcs.01655 DOI: 10.1242/jcs.01655
Bolós M, Pallas-Bazarra N, Terreros-Roncal J et al (2017) Soluble tau has devastating effects on the structural plasticity of hippocampal granule neurons. Transl Psychiatry 7:1267. 10.1038/s41398-017-0013-6 DOI: 10.1038/s41398-017-0013-6
Bolós M, Llorens-Martín M, Perea J et al (2017) Absence of CX3CR1 impairs the internalization of tau by microglia. Mol Neurodegener 12:59. 10.1186/s13024-017-0200-1 DOI: 10.1186/s13024-017-0200-1
Gómez-Ramos A, Díaz-Hernández M, Cuadros R et al (2006) Extracellular tau is toxic to neuronal cells. FEBS Lett 580:4842–4850. 10.1016/j.febslet.2006.07.078 DOI: 10.1016/j.febslet.2006.07.078
Gabandé-Rodríguez E, Keane L, Capasso M (2020) Microglial phagocytosis in aging and Alzheimer’s disease. J Neurosci Res 98:284–298. 10.1002/jnr.24419 DOI: 10.1002/jnr.24419
Brunello CA, Merezhko M, Uronen R-L, Huttunen HJ (2019) Mechanisms of secretion and spreading of pathological tau protein. Cell Mol Life Sci. 10.1007/s00018-019-03349-1 DOI: 10.1007/s00018-019-03349-1
Elliott JA, Winn WC (1986) Treatment of alveolar macrophages with cytochalasin D inhibits uptake and subsequent growth of Legionella pneumophila. Infect Immun 51:31–36 DOI: 10.1128/iai.51.1.31-36.1986
Zhang Y, Chen K, Sloan SA et al (2014) An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex. J Neurosci 34:11929–11947. 10.1523/JNEUROSCI.1860-14.2014 DOI: 10.1523/JNEUROSCI.1860-14.2014
Zhang Y, Sloan SA, Clarke LE et al (2016) Purification and characterization of progenitor and mature human astrocytes reveals transcriptional and functional differences with mouse. Neuron 89:37–53. 10.1016/j.neuron.2015.11.013 DOI: 10.1016/j.neuron.2015.11.013
Yamada K, Cirrito JR, Stewart FR et al (2011) In vivo microdialysis reveals age-dependent decrease of brain interstitial fluid tau levels in P301S human tau transgenic mice. J Neurosci 31:13110–13117. 10.1523/JNEUROSCI.2569-11.2011 DOI: 10.1523/JNEUROSCI.2569-11.2011
Vaughan DW, Peters A (1974) Neuroglial cells in the cerebral cortex of rats from young adulthood to old age: an electron microscope study. J Neurocytol 3:405–429. 10.1007/bf01098730 DOI: 10.1007/bf01098730
Stancu I-C, Cremers N, Vanrusselt H et al (2019) Aggregated tau activates NLRP3-ASC inflammasome exacerbating exogenously seeded and non-exogenously seeded tau pathology in vivo. Acta Neuropathol 137:599–617. 10.1007/s00401-018-01957-y DOI: 10.1007/s00401-018-01957-y
Davalos D, Grutzendler J, Yang G et al (2005) ATP mediates rapid microglial response to local brain injury in vivo. Nat Neurosci 8:752–758. 10.1038/nn1472 DOI: 10.1038/nn1472
Nimmerjahn A, Kirchhoff F, Helmchen F (2005) Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308:1314–1318. 10.1126/science.1110647 DOI: 10.1126/science.1110647
Guay J, Lambert H, Gingras-Breton G et al (1997) Regulation of actin filament dynamics by p38 map kinase-mediated phosphorylation of heat shock protein 27. J Cell Sci 110:357–368 DOI: 10.1242/jcs.110.3.357
Jadhav S, Avila J, Schöll M et al (2019) A walk through tau therapeutic strategies. Acta Neuropathol Commun 7:22. 10.1186/s40478-019-0664-z DOI: 10.1186/s40478-019-0664-z
Kelleher I, Garwood C, Hanger DP et al (2007) Kinase activities increase during the development of tauopathy in htau mice. J Neurochem 103:2256–2267. 10.1111/j.1471-4159.2007.04930.x DOI: 10.1111/j.1471-4159.2007.04930.x
Bhaskar K, Konerth M, Kokiko-Cochran ON et al (2010) Regulation of tau pathology by the microglial fractalkine receptor. Neuron 68:19–31. 10.1016/j.neuron.2010.08.023 DOI: 10.1016/j.neuron.2010.08.023
Lee S, Xu G, Jay TR et al (2014) Opposing effects of membrane-anchored CX3CL1 on amyloid and tau pathologies via the p38 MAPK pathway. J Neurosci 34:12538–12546. 10.1523/JNEUROSCI.0853-14.2014 DOI: 10.1523/JNEUROSCI.0853-14.2014
Xia Z, Dickens M, Raingeaud J et al (1995) Opposing effects of ERK and JNK-p38 MAP kinases on apoptosis. Science 270:1326–1331. 10.1126/science.270.5240.1326 DOI: 10.1126/science.270.5240.1326
Mosher KI, Wyss-Coray T (2014) Microglial dysfunction in brain aging and Alzheimer’s disease. Biochem Pharmacol 88:594–604. 10.1016/j.bcp.2014.01.008 DOI: 10.1016/j.bcp.2014.01.008
Pluvinage JV, Haney MS, Smith BAH et al (2019) CD22 blockade restores homeostatic microglial phagocytosis in ageing brains. Nature 568:187–192. 10.1038/s41586-019-1088-4 DOI: 10.1038/s41586-019-1088-4
Reed-Geaghan EG, Savage JC, Hise AG, Landreth GE (2009) CD14 and Toll-like receptors 2 and 4 are required for fibrillar A-stimulated microglial activation. J Neurosci 29:11982–11992. 10.1523/JNEUROSCI.3158-09.2009 DOI: 10.1523/JNEUROSCI.3158-09.2009
Gerrits E, Brouwer N, Kooistra SM et al (2021) Distinct amyloid-β and tau-associated microglia profiles in Alzheimer’s disease. Acta Neuropathol 141:681–696. 10.1007/s00401-021-02263-w DOI: 10.1007/s00401-021-02263-w
Andersson CR, Falsig J, Stavenhagen JB et al (2019) Antibody-mediated clearance of tau in primary mouse microglial cultures requires Fcγ-receptor binding and functional lysosomes. Sci Rep 9:1–12. 10.1038/s41598-019-41105-4 DOI: 10.1038/s41598-019-41105-4
Cavalli V, Vilbois F, Corti M et al (2001) The stress-induced MAP kinase p38 regulates endocytic trafficking via the GDI:Rab5 complex. Mol Cell 7:421–432. 10.1016/S1097-2765(01)00189-7 DOI: 10.1016/S1097-2765(01)00189-7
Fratti RA, Chua J, Deretic V (2003) Induction of p38 mitogen-activated protein kinase reduces early endosome autoantigen 1 (EEA1) recruitment to phagosomal membranes. J Biol Chem 278:46961–46967. 10.1074/jbc.M305225200 DOI: 10.1074/jbc.M305225200
Pelkmans L, Fava E, Grabner H et al (2005) Genome-wide analysis of human kinases in clathrin- and caveolae/raft-mediated endocytosis. Nature 436:78–86. 10.1038/nature03571 DOI: 10.1038/nature03571
Yang C, Zhu Z, Tong BCK et al (2020) A stress response p38 MAP kinase inhibitor SB202190 promoted TFEB/TFE3-dependent autophagy and lysosomal biogenesis independent of p38. Redox Biol 32:101445. 10.1016/j.redox.2020.101445 DOI: 10.1016/j.redox.2020.101445
Jiang S, Bhaskar K (2020) Degradation and transmission of tau by autophagic-endolysosomal networks and potential therapeutic targets for tauopathy. Front Mol Neurosci 13:1–19. 10.3389/fnmol.2020.586731 DOI: 10.3389/fnmol.2020.586731
Perlmutter LS, Barron E, Chui HC (1990) Morphologic association between microglia and senile plaque amyloid in Alzheimer’s disease. Neurosci Lett 119:32–36. 10.1016/0304-3940(90)90748-x DOI: 10.1016/0304-3940(90)90748-x
Du YS, Chen X, Fu J et al (1996) RAGE and amyloid-beta peptide neurotoxicity in Alzheimer’s disease. Nature 382:685–691. 10.1038/382685a0 DOI: 10.1038/382685a0
Bolmont T, Haiss F, Eicke D et al (2008) Dynamics of the microglial/amyloid interaction indicate a role in plaque maintenance. J Neurosci 28:4283–4292. 10.1523/JNEUROSCI.4814-07.2008 DOI: 10.1523/JNEUROSCI.4814-07.2008
Meyer-Luehmann M, Spires-Jones TL, Prada C et al (2008) Rapid appearance and local toxicity of amyloid-beta plaques in a mouse model of Alzheimer’s disease. Nature 451:720–724. 10.1038/nature06616 DOI: 10.1038/nature06616
Behrendt A, Bichmann M, Ercan-Herbst E et al (2019) Asparagine endopeptidase cleaves tau at N167 after uptake into microglia. Neurobiol Dis 130:104518. 10.1016/j.nbd.2019.104518 DOI: 10.1016/j.nbd.2019.104518
Damani MR, Zhao L, Fontainhas AM et al (2011) Age-related alterations in the dynamic behavior of microglia. Aging Cell 10:263–276. 10.1111/j.1474-9726.2010.00660.x DOI: 10.1111/j.1474-9726.2010.00660.x
Fang Y, Wang J, Yao L et al (2018) The adhesion and migration of microglia to β-amyloid (Aβ) is decreased with aging and inhibited by Nogo/NgR pathway. J Neuroinflammation 15:210. 10.1186/s12974-018-1250-1 DOI: 10.1186/s12974-018-1250-1
Benndorf R, Hayeß K, Ryazantsev S et al (1994) Phosphorylation and supramolecular organization of murine small heat shock protein HSP25 abolish its actin polymerization-inhibiting activity. J Biol Chem 269:20780–20784. 10.1016/s0021-9258(17)32060-4 DOI: 10.1016/s0021-9258(17)32060-4
Arrasate M, Pérez M, Avila J (2000) Tau dephosphorylation at tau-1 site correlates with its association to cell membrane. Neurochem Res 25:43–50. 10.1023/A:1007583214722 DOI: 10.1023/A:1007583214722
Rauch JN, Luna G, Guzman E et al (2020) LRP1 is a master regulator of tau uptake and spread. Nature 580:381–385. 10.1038/s41586-020-2156-5 DOI: 10.1038/s41586-020-2156-5
Wang P, Ye Y (2021) Filamentous recombinant human tau activates primary astrocytes via an integrin receptor complex. Nat Commun 12:95. 10.1038/s41467-020-20322-w DOI: 10.1038/s41467-020-20322-w
Zhuang Z-Y, Kawasaki Y, Tan P-H et al (2007) Role of the CX3CR1/p38 MAPK pathway in spinal microglia for the development of neuropathic pain following nerve injury-induced cleavage of fractalkine. Brain Behav Immun 21:642–651. 10.1016/j.bbi.2006.11.003 DOI: 10.1016/j.bbi.2006.11.003
Doens D, Fernández PL (2014) Microglia receptors and their implications in the response to amyloid β for Alzheimer’s disease pathogenesis. J Neuroinflammation 11:48. 10.1186/1742-2094-11-48 DOI: 10.1186/1742-2094-11-48
Momtazmanesh S, Perry G, Rezaei N (2020) Toll-like receptors in Alzheimer’s disease. J Neuroimmunol 348:577362. 10.1016/j.jneuroim.2020.577362 DOI: 10.1016/j.jneuroim.2020.577362
Gunawardana CG, Mehrabian M, Wang X et al (2015) The human tau interactome: binding to the ribonucleoproteome, and impaired binding of the proline-to-leucine mutant at position 301 (P301L) to chaperones and the proteasome. Mol Cell Proteomics 14:3000–3014. 10.1074/mcp.M115.050724 DOI: 10.1074/mcp.M115.050724
Stefanoska K, Volkerling A, Bertz J et al (2018) An N-terminal motif unique to primate tau enables differential protein-protein interactions. J Biol Chem 293:3710–3719. 10.1074/jbc.RA118.001784 DOI: 10.1074/jbc.RA118.001784
Luck K, Kim D-K, Lambourne L et al (2020) A reference map of the human binary protein interactome. Nature. 10.1038/s41586-020-2188-x DOI: 10.1038/s41586-020-2188-x
Tomida T, Takekawa M, Saito H (2015) Oscillation of p38 activity controls efficient pro-inflammatory gene expression. Nat Commun 6:4–6. 10.1038/ncomms9350 DOI: 10.1038/ncomms9350
Kumar GS, Clarkson MW, Kunze MBA et al (2018) Dynamic activation and regulation of the mitogen-activated protein kinase p38. Proc Natl Acad Sci USA 115:4655–4660. 10.1073/pnas.1721441115 DOI: 10.1073/pnas.1721441115
Munoz L, Ralay Ranaivo H, Roy SM et al (2007) A novel p38 alpha MAPK inhibitor suppresses brain proinflammatory cytokine up-regulation and attenuates synaptic dysfunction and behavioral deficits in an Alzheimer’s disease mouse model. J Neuroinflammation 4:21. 10.1186/1742-2094-4-21 DOI: 10.1186/1742-2094-4-21
Roy SM, Grum-Tokars VL, Schavocky JP et al (2015) Targeting human central nervous system protein kinases: An isoform selective p38αMAPK inhibitor that attenuates disease progression in Alzheimer’s disease mouse models. ACS Chem Neurosci 6:666–680. 10.1021/acschemneuro.5b00002 DOI: 10.1021/acschemneuro.5b00002
Gee MS, Son SH, Jeon SH et al (2020) A selective p38α/β MAPK inhibitor alleviates neuropathology and cognitive impairment, and modulates microglia function in 5XFAD mouse. Alzheimers Res Ther 12:45. 10.1186/s13195-020-00617-2 DOI: 10.1186/s13195-020-00617-2
Maphis N, Jiang S, Xu G et al (2016) Selective suppression of the α isoform of p38 MAPK rescues late-stage tau pathology. Alzheimers Res Ther 8:54. 10.1186/s13195-016-0221-y DOI: 10.1186/s13195-016-0221-y
Prins ND, Harrison JE, Chu H-M et al (2021) A phase 2 double-blind placebo-controlled 24-week treatment clinical study of the p38 alpha kinase inhibitor neflamapimod in mild Alzheimer’s disease. Alzheimers Res Ther 13:106. 10.1186/s13195-021-00843-2 DOI: 10.1186/s13195-021-00843-2
