Plaque associated microglia hyper-secrete extracellular vesicles and accelerate tau propagation in a humanized APP mouse model
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Abstract
Abstract Background Recent studies suggest that microglia contribute to tau pathology progression in Alzheimer’s disease. Amyloid plaque accumulation transforms microglia, the primary innate immune cells in the brain, into neurodegenerative microglia (MGnD), which exhibit enhanced phagocytosis of plaques, apoptotic neurons and dystrophic neurites containing aggregated and phosphorylated tau (p-tau). It remains unclear how microglia promote disease progression while actively phagocytosing pathological proteins, therefore ameliorating pathology. Methods Adeno-associated virus expressing P301L tau mutant (AAV-P301L-tau) was stereotaxically injected into the medial entorhinal cortex (MEC) in C57BL/6 (WT) and humanized APP mutant knock-in homozygote ( App NL-G-F ) mice at 5 months of age. Mice were fed either chow containing a colony stimulating factor-1 receptor inhibitor (PLX5622) or control chow from 4 to 6 months of age to test the effect of microglia depletion. Animals were tested at 6 months of age for immunofluorescence, biochemistry, and FACS of microglia. In order to monitor microglial extracellular vesicle secretion in vivo, a novel lentiviral EV reporter system was engineered to express mEmerald-CD9 (mE-CD9) specifically in microglia, which was injected into the same region of MEC. Results Expressing P301L tau mutant in the MEC induced tau propagation to the granule cell layer of the hippocampal dentate gyrus, which was significantly exacerbated in App NL-G-F mice compared to WT control mice. Administration of PLX5622 depleted nearly all microglia in mouse brains and dramatically reduced propagation of p-tau in WT and to a greater extent in App NL-G-F mice, although it increased plaque burden and plaque-associated p-tau + dystrophic neurites. Plaque-associated MGnD microglia strongly expressed an EV marker, tumor susceptibility gene 101, indicative of heightened synthesis of EVs. Intracortical injection of mE-CD9 lentivirus successfully induced microglia-specific expression of mE-CD9 + EV particles, which were significantly enhanced in Mac2 + MGnD microglia compared to Mac2 − homeostatic microglia. Finally, consecutive intracortical injection of mE-CD9 lentivirus and AAV-P301L-tau into App NL-G-F mice revealed encapsulation of p-tau in microglia-specific mE-CD9 + EVs as determined by super-resolution microscopy and immuno-electron microscopy. Discussion Our findings suggest that MGnD microglia hyper-secrete p-tau + EVs while compacting Aβ plaques and clearing NP tau, which we propose as a novel mechanistic link between amyloid plaque deposition and exacerbation of tau propagation in App NL-G-F mice.
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Amyloid-β-associated microglia secrete extracellular vesicles that contain phosphorylated tau, and their depletion abrogated tau propagation.
“Amyloid-β–associated microglia were shown to secrete extracellular vesicles that contain phosphorylated tau and their depletion abrogated tau propagation (Clayton et al., 2021).”
From A novel molecular class that recruits HDAC/MECP2 complexes to PU.1 motifs reduces neuroinflammation (2023) · cites this paper as Clayton et al., 2021
The Discussion (‘Microglia depletion and tauopathy’; page unavailable) reports that plaque-associated microglia secrete extracellular vesicles containing phosphorylated tau. The Results (‘Enhanced tau propagation and its reduction by CSF1R inhibition in AppNL-G-F mice’; page unavailable) say microglial depletion effectively suppressed tau propagation in the mouse model, but do not establish that it abrogated propagation entirely. (LLM, conf=0.86)
Experimental — accuracy not yet measuredMicroglia play essential role in plaque compaction between 4-6 months in mice.
“demonstrating that microglia play an essential role in plaque compaction between four to six months of age in mice [61]”
From Microglia and monocytes in inflammatory CNS disease: integrating phenotype and function (2022) · cites this paper as [61]
The Results section (‘Microglia depletion increases plaque deposition’; page unavailable) strongly suggests that microglia have a significant role in plaque compaction in AppNL-G-F mice between 4 and 6 months of age. The claim overstates that finding as a demonstrated, essential role and omits the specific mouse model. (LLM, conf=0.86)
Experimental — accuracy not yet measuredMicroglia near amyloid plaques are three times as phagocytic and three times more likely to release tau-containing extracellular vesicles.
“microglia were shown to be three times as phagocytic and three times more likely to release tau-containing extracellular vesicles when situated near amyloid plaques [61]”
From Microglia and monocytes in inflammatory CNS disease: integrating phenotype and function (2022) · cites this paper as [61]
The Results section (‘P-tau is encapsulated within microglia-specific EVs’) reports that MGnD microglia released roughly three times as many extracellular vesicles as homeostatic microglia, and that they internalized more p-tau and released more p-tau-containing vesicles. It does not report threefold phagocytosis or a threefold greater likelihood of releasing tau-containing vesicles; the threefold figure describes the number of vesicles released. (LLM, conf=0.88)
Experimental — accuracy not yet measuredIn the same study, an increase in plaque-associated tau in dystrophic neurites was found, indicating that microglia play a complex role in both the spread of tau and clearance of neuronal debris associated with pathological tau.
“However, in the same study, an increase in plaque-associated tau in dystrophic neurites was found, indicating that microglia play a complex role in both the spread of tau and clearance of neuronal debris associated with pathological tau.”
From A novel molecular class that recruits HDAC/MECP2 complexes to PU.1 motifs reduces neuroinflammation (2023) · cites this paper as Clayton et al., 2021
Microglia depletion in 4-month-old APPNL−G−F mice resulted in reduced plaque compaction and increased plaque volume, number, and size.
“microglia depletion in four-month-old humanized APP mutant knock-in homozygote (APPNL−G−F) mice resulted in reduced plaque compaction and increased plaque volume, number, and size”
From Microglia and monocytes in inflammatory CNS disease: integrating phenotype and function (2022) · cites this paper as [61]
Microglia are implicated in pathological spreading of tau via release of extracellular vesicles.
“Microglia have also been implicated in the pathological spreading of tau via the release of extracellular vesicles [12, 61, 328]”
From Microglia and monocytes in inflammatory CNS disease: integrating phenotype and function (2022) · cites this paper as [61]
Enhanced tau propagation in mice with amyloidosis compared to wild-type without amyloidosis.
“This was associated with enhanced tau propagation in mice with amyloidosis, compared to wild-type mice without amyloidosis [61]”
From Microglia and monocytes in inflammatory CNS disease: integrating phenotype and function (2022) · cites this paper as [61]
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Cites
A Unique Microglia Type Associated with Restricting Development of Alzheimer’s Disease
Keren-Shaul, H., Spinrad, A., Weiner, A., Matcovitch-Natan, O., Dvir-Szternfeld, R., Ulland, T. K., David, E., Baruch, K., Lara-Astaiso, D., Toth, B., et al. (2017) · Cell · doi:10.1016/j.cell.2017.05.018 · Cited by 5,493 · see citing works
Synaptic Pruning by Microglia Is Necessary for Normal Brain Development
Paolicelli, R. C., Bolasco, G., Pagani, F., Maggi, L., Scianni, M., Panzanelli, P., Giustetto, M., Ferreira, T. A., Guiducci, E., Dumas, L., et al. (2011) · Science · doi:10.1126/science.1202529 · Cited by 4,244 · see citing works
Microglia Sculpt Postnatal Neural Circuits in an Activity and Complement-Dependent Manner
Schafer, D. P., Lehrman, E. K., Kautzman, A. G., Koyama, R., Mardinly, A. R., Yamasaki, R., Ransohoff, R. M., Greenberg, M. E., Barres, B. A., & Stevens, B. (2012) · Neuron · doi:10.1016/j.neuron.2012.03.026 · Cited by 4,089 · see citing works
Complement and microglia mediate early synapse loss in Alzheimer mouse models
Hong, S., Beja-Glasser, V. F., Nfonoyim, B. M., Frouin, A., Li, S., Ramakrishnan, S., Merry, K. M., Shi, Q., Rosenthal, A., Barres, B. A., et al. (2016) · Science · doi:10.1126/science.aad8373 · Cited by 3,343 · cited 1× · see citing works
“It is well known that microglia actively phagocytose synapses by synaptic tagging with complements (C1q and C3) [50–52], which also play an important role in Aβ-induced synaptic loss [53].”
BackgroundKrasemann, S., Madore, C., Cialic, R., Baufeld, C., Calcagno, N., El Fatimy, R., Beckers, L., O’Loughlin, E., Xu, Y., Fanek, Z., et al. (2017) · Immunity · doi:10.1016/j.immuni.2017.08.008 · Cited by 2,979 · see citing works
Self-citationIdentification of a unique TGF-β–dependent molecular and functional signature in microglia
Butovsky, O., Jedrychowski, M. P., Moore, C. S., Cialic, R., Lanser, A. J., Gabriely, G., Koeglsperger, T., Dake, B., Wu, P. M., Doykan, C. E., et al. (2014) · Nature Neuroscience · doi:10.1038/nn.3599 · Cited by 2,543 · see citing works
Elmore, M. R. P., Najafi, A. R., Koike, M. A., Dagher, N. N., Spangenberg, E. E., Rice, R. A., Kitazawa, M., Matusow, B., Nguyen, H., West, B. L., et al. (2014) · Neuron · doi:10.1016/j.neuron.2014.02.040 · Cited by 1,968 · see citing works
Depletion of microglia and inhibition of exosome synthesis halt tau propagation
Asai, H., Ikezu, S., Tsunoda, S., Medalla, M., Luebke, J., Haydar, T., Wolozin, B., Butovsky, O., Kügler, S., & Ikezu, T. (2015) · Nature Neuroscience · doi:10.1038/nn.4132 · Cited by 1,591 · see citing works
Self-citationThe microglial sensome revealed by direct RNA sequencing
Hickman, S. E., Kingery, N. D., Ohsumi, T. K., Borowsky, M. L., Wang, L.-C., Means, T. K., & El Khoury, J. (2013) · Nature Neuroscience · doi:10.1038/nn.3554 · Cited by 1,511 · see citing works
NLRP3 inflammasome activation drives tau pathology
Ising, C., Venegas, C., Zhang, S., Scheiblich, H., Schmidt, S. V., Vieira-Saecker, A., Schwartz, S., Albasset, S., McManus, R. M., Tejera, D., et al. (2019) · Nature · doi:10.1038/s41586-019-1769-z · Cited by 1,487 · see citing works
Disease-Associated Microglia: A Universal Immune Sensor of Neurodegeneration
Deczkowska, A., Keren-Shaul, H., Weiner, A., Colonna, M., Schwartz, M., & Amit, I. (2018) · Cell · doi:10.1016/j.cell.2018.05.003 · Cited by 1,474 · see citing works
Single App knock-in mouse models of Alzheimer’s disease
Saito, T., Matsuba, Y., Mihira, N., Takano, J., Nilsson, P., Itohara, S., Iwata, N., & Saido, T. C. (2014) · Nature Neuroscience · doi:10.1038/nn.3697 · Cited by 1,447 · see citing works
Self-citationSimard, A. R., Soulet, D., Gowing, G., Julien, J.-P., & Rivest, S. (2006) · Neuron · doi:10.1016/j.neuron.2006.01.022 · Cited by 1,265 · see citing works
Role of Pro-Inflammatory Cytokines Released from Microglia in Neurodegenerative Diseases
Smith, J. A., Das, A., Ray, S. K., & Banik, N. L. (2012) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2011.10.004 · Cited by 1,165 · see citing works
Trans-Synaptic Spread of Tau Pathology In Vivo
Liu, L., Drouet, V., Wu, J., Witter, M. P., Small, S. A., Clelland, C. L. T., & Duff, K. (2012) · PLoS ONE · doi:10.1371/journal.pone.0031302 · Cited by 994 · see citing works
Spangenberg, E., Severson, P. L., Hohsfield, L. A., Crapser, J., Zhang, J., Burton, E. A., Zhang, Y., Spevak, W., Lin, J., Phan, N. Y., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-11674-z · Cited by 939 · see citing works
Scavenger receptor-mediated adhesion of microglia to β-amyloid fibrils
Khoury, J. E., Hickman, S. E., Thomas, C. A., Cao, L., Silverstein, S. C., & Loike, J. D. (1996) · Nature · doi:10.1038/382716a0 · Cited by 727 · see citing works
The role of microglia in amyloid clearance from the AD brain
Lee, C. Y. D., & Landreth, G. E. (2010) · Journal of Neural Transmission · doi:10.1007/s00702-010-0433-4 · Cited by 701 · see citing works
Kitazawa, M., Oddo, S., Yamasaki, T. R., Green, K. N., & LaFerla, F. M. (2005) · The Journal of Neuroscience · doi:10.1523/jneurosci.2868-05.2005 · Cited by 697 · see citing works
Spangenberg, E. E., Lee, R. J., Najafi, A. R., Rice, R. A., Elmore, M. R. P., Blurton-Jones, M., West, B. L., & Green, K. N. (2016) · Brain · doi:10.1093/brain/aww016 · Cited by 695 · see citing works
Phagocytosis of Microglia in the Central Nervous System Diseases
Fu, R., Shen, Q., Xu, P., Luo, J. J., & Tang, Y. (2014) · Molecular Neurobiology · doi:10.1007/s12035-013-8620-6 · Cited by 646 · see citing works
He, Z., Guo, J. L., McBride, J. D., Narasimhan, S., Kim, H., Changolkar, L., Zhang, B., Gathagan, R. J., Yue, C., Dengler, C., et al. (2018) · Nature Medicine · doi:10.1038/nm.4443 · Cited by 645 · see citing works
Butowski, N. A., Colman, H., de Groot, J., Omuro, A. M. P., Nayak, L., Wen, P. Y., Cloughesy, T. F., Marimuthu, A., Haidar, S., Perry, A., et al. (2015) · Neuro-Oncology · doi:10.1093/neuonc/nov245 · Cited by 593 · see citing works
Ito, D., Tanaka, K., Suzuki, S., Dembo, T., & Fukuuchi, Y. (2001) · Stroke · doi:10.1161/01.str.32.5.1208 · Cited by 593 · see citing works
Dejanovic, B., Huntley, M. A., De Mazière, A., Meilandt, W. J., Wu, T., Srinivasan, K., Jiang, Z., Gandham, V., Friedman, B. A., Ngu, H., et al. (2018) · Neuron · doi:10.1016/j.neuron.2018.10.014 · Cited by 575 · see citing works
Li, Y., Liu, L., Barger, S. W., & Griffin, W. S. T. (2003) · The Journal of Neuroscience · doi:10.1523/jneurosci.23-05-01605.2003 · Cited by 563 · see citing works
Olmos-Alonso, A., Schetters, S. T. T., Sri, S., Askew, K., Mancuso, R., Vargas-Caballero, M., Holscher, C., Perry, V. H., & Gomez-Nicola, D. (2016) · Brain · doi:10.1093/brain/awv379 · Cited by 532 · see citing works
Dagher, N. N., Najafi, A. R., Kayala, K. M. N., Elmore, M. R. P., White, T. E., Medeiros, R., West, B. L., & Green, K. N. (2015) · Journal of Neuroinflammation · doi:10.1186/s12974-015-0366-9 · Cited by 505 · see citing works
Microglia drive APOE-dependent neurodegeneration in a tauopathy mouse model
Shi, Y., Manis, M., Long, J., Wang, K., Sullivan, P. M., Remolina Serrano, J., Hoyle, R., & Holtzman, D. M. (2019) · Journal of Experimental Medicine · doi:10.1084/jem.20190980 · Cited by 448 · see citing works
Microglial Phagocytosis of Fibrillar β-Amyloid through a β1Integrin-Dependent Mechanism
Koenigsknecht-Talboo, J., & Landreth, G. E. (2004) · Journal of Neuroscience · doi:10.1523/jneurosci.2557-04.2004 · Cited by 444 · see citing works
Local externalization of phosphatidylserine mediates developmental synaptic pruning by microglia
Scott‐Hewitt, N., Perrucci, F., Morini, R., Erreni, M., Mahoney, M., Witkowska, A., Carey, A. E., Faggiani, E., Schuetz, L. T., Mason, S., et al. (2020) · The EMBO Journal · doi:10.15252/embj.2020105380 · Cited by 425 · see citing works
A Dramatic Increase of C1q Protein in the CNS during Normal Aging
Stephan, A. H., Madison, D. V., Mateos, J. M., Fraser, D. A., Lovelett, E. A., Coutellier, L., Kim, L., Tsai, H.-H., Huang, E. J., Rowitch, D. H., et al. (2013) · The Journal of Neuroscience · doi:10.1523/jneurosci.1333-13.2013 · Cited by 423 · see citing works
Sosna, J., Philipp, S., Albay, R., Reyes-Ruiz, J. M., Baglietto-Vargas, D., LaFerla, F. M., & Glabe, C. G. (2018) · Molecular Neurodegeneration · doi:10.1186/s13024-018-0244-x · Cited by 406 · see citing works
Formation and maintenance of Alzheimer's disease β-amyloid plaques in the absence of microglia
Grathwohl, S. A., Kälin, R. E., Bolmont, T., Prokop, S., Winkelmann, G., Kaeser, S. A., Odenthal, J., Radde, R., Eldh, T., Gandy, S., et al. (2009) · Nature Neuroscience · doi:10.1038/nn.2432 · Cited by 401 · see citing works
Extracellular vesicles as mediators of neuron-glia communication
Frühbeis, C., Fröhlich, D., Kuo, W. P., & Krämer‐Albers, E. (2013) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2013.00182 · Cited by 383 · see citing works
Zhong, L., Xu, Y., Zhuo, R., Wang, T., Wang, K., Huang, R., Wang, D., Gao, Y., Zhu, Y., Sheng, X., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-09118-9 · Cited by 371 · see citing works
The perforant path: projections from the entorhinal cortex to the dentate gyrus
Witter, M. P. (2007) · Progress in brain research · doi:10.1016/s0079-6123(07)63003-9 · Cited by 358 · see citing works
Butovsky, O., Jedrychowski, M. P., Cialic, R., Krasemann, S., Murugaiyan, G., Fanek, Z., Greco, D. J., Wu, P. M., Doykan, C. E., Kiner, O., et al. (2015) · Annals of Neurology · doi:10.1002/ana.24304 · Cited by 358 · see citing works
Boza-Serrano, A., Ruiz, R., Sanchez-Varo, R., García-Revilla, J., Yang, Y., Jimenez-Ferrer, I., Paulus, A., Wennström, M., Vilalta, A., Allendorf, D., et al. (2019) · Acta Neuropathologica · doi:10.1007/s00401-019-02013-z · Cited by 357 · see citing works
Microglia-Mediated Synapse Loss in Alzheimer's Disease
Rajendran, L., & Paolicelli, R. C. (2018) · The Journal of Neuroscience · doi:10.1523/jneurosci.1136-17.2017 · Cited by 355 · see citing works
Cell-specific deletion of C1qa identifies microglia as the dominant source of C1q in mouse brain
Fonseca, M. I., Chu, S.-H., Hernandez, M. X., Fang, M. J., Modarresi, L., Selvan, P., MacGregor, G. R., & Tenner, A. J. (2017) · Journal of Neuroinflammation · doi:10.1186/s12974-017-0814-9 · Cited by 337 · see citing works
TREM2 function impedes tau seeding in neuritic plaques
Leyns, C. E. G., Gratuze, M., Narasimhan, S., Jain, N., Koscal, L. J., Jiang, H., Manis, M., Colonna, M., Lee, V. M. Y., Ulrich, J. D., et al. (2019) · Nature Neuroscience · doi:10.1038/s41593-019-0433-0 · Cited by 332 · see citing works
Antonucci, F., Turola, E., Riganti, L., Caleo, M., Gabrielli, M., Perrotta, C., Novellino, L., Clementi, E., Giussani, P., Viani, P., et al. (2012) · The EMBO Journal · doi:10.1038/emboj.2011.489 · Cited by 328 · see citing works
Island Cells Control Temporal Association Memory
北村, 貴., Pignatelli, M., Suh, J., Kohara, K., Yoshiki, A., Abe, K., & Tonegawa, S. (2014) · Science · doi:10.1126/science.1244634 · Cited by 327 · see citing works
Tunneling nanotube (TNT)-mediated neuron-to neuron transfer of pathological Tau protein assemblies
Tardivel, M., Bégard, S., Bousset, L., Dujardin, S., Coens, A., Melki, R., Buée, L., & Colin, M. (2016) · Acta Neuropathologica Communications · doi:10.1186/s40478-016-0386-4 · Cited by 305 · see citing works
The role of microglia in processing and spreading of bioactive tau seeds in Alzheimer’s disease
Hopp, S. C., Lin, Y., Oakley, D., Roe, A. D., DeVos, S. L., Hanlon, D., & Hyman, B. T. (2018) · Journal of Neuroinflammation · doi:10.1186/s12974-018-1309-z · Cited by 286 · see citing works
Synaptic Tau Seeding Precedes Tau Pathology in Human Alzheimer’s Disease Brain
DeVos, S. L., Corjuc, B. T., Oakley, D. H., Nobuhara, C. K., Bannon, R. N., Chase, A., Commins, C., Gonzalez, J. A., Dooley, P. M., Frosch, M. P., et al. (2018) · Frontiers in Neuroscience · doi:10.3389/fnins.2018.00267 · Cited by 285 · see citing works
Rice, R. A., Spangenberg, E. E., Yamate-Morgan, H., Lee, R. J., Arora, R. P. S., Hernandez, M. X., Tenner, A. J., West, B. L., & Green, K. N. (2015) · Journal of Neuroscience · doi:10.1523/jneurosci.0336-15.2015 · Cited by 270 · see citing works
Formation and maintenance of Alzheimer’s disease beta-amyloid plaques in the absence of microglia
Grathwohl, S. A., Kälin, R., Bolmont, T., Prokop, S., Winkelmann, G., Kaeser, S. A., Odenthal, J., Radde, R., Eldh, T., Gandy, S. E., et al. (2010) · e-Neuroforum · doi:10.1515/nf-2010-0107 · Cited by 269 · see citing works
Pisanu, A., Lecca, D., Mulas, G., Wardas, J., Simbula, G., Spiga, S., & Carta, A. R. (2014) · Neurobiology of Disease · doi:10.1016/j.nbd.2014.08.011 · Cited by 268 · see citing works
Amyloid accelerates tau propagation and toxicity in a model of early Alzheimer’s disease
Pooler, A. M., Polydoro, M., Maury, E. A., Nicholls, S. B., Reddy, S. M., Wegmann, S., William, C., Saqran, L., Cagsal-Getkin, O., Pitstick, R., et al. (2015) · Acta Neuropathologica Communications · doi:10.1186/s40478-015-0199-x · Cited by 236 · see citing works
The Role of Microglia and the Nlrp3 Inflammasome in Alzheimer's Disease
Hanslik, K. L., & Ulland, T. K. (2020) · Frontiers in Neurology · doi:10.3389/fneur.2020.570711 · Cited by 236 · see citing works
CSF1R inhibitor JNJ-40346527 attenuates microglial proliferation and neurodegeneration in P301S mice
Mancuso, R., Fryatt, G., Cleal, M., Obst, J., Pipi, E., Monzón-Sandoval, J., Ribe, E., Winchester, L., Webber, C., Nevado, A., et al. (2019) · Brain · doi:10.1093/brain/awz241 · Cited by 235 · see citing works
Hurtado, D. E., Molina-Porcel, L., Iba, M., Aboagye, A. K., Paul, S. M., Trojanowski, J. Q., & Lee, V. M.-Y. (2010) · The American Journal of Pathology · doi:10.2353/ajpath.2010.100346 · Cited by 222 · see citing works
Jüttner, J., Szabo, A., Gross-Scherf, B., Morikawa, R. K., Rompani, S. B., Hantz, P., Szikra, T., Esposti, F., Cowan, C. S., Bharioke, A., et al. (2019) · Nature Neuroscience · doi:10.1038/s41593-019-0431-2 · Cited by 218 · see citing works
Muraoka, S., DeLeo, A. M., Sethi, M. K., Takamatsu-Yukawa, K., Yang, Z., Ko, J., Hogan, J., Ruan, Z., You, Y., Wang, Y., et al. (2020) · Alzheimer s & Dementia · doi:10.1002/alz.12089 · Cited by 189 · see citing works
Self-citationCasali, B. T., MacPherson, K. P., Reed-Geaghan, E. G., & Landreth, G. E. (2020) · Neurobiology of Disease · doi:10.1016/j.nbd.2020.104956 · Cited by 186 · see citing works
Kügler, S., Meyn, L., Holzmüller, H., Gerhardt, E., Isenmann, S., Schulz, J. B., & Bähr, M. (2001) · Molecular and Cellular Neuroscience · doi:10.1006/mcne.2000.0929 · Cited by 182 · see citing works
Clearance of Amyloid-β Peptides By Microglia and Macrophages: the Issue of What, When and Where
Lai, A. Y., & McLaurin, J. (2012) · Future Neurology · doi:10.2217/fnl.12.6 · Cited by 161 · see citing works
Microglia limit the expansion of β-amyloid plaques in a mouse model of Alzheimer’s disease
Zhao, R., Hu, W., Tsai, J., Li, W., & Gan, W.-B. (2017) · Molecular Neurodegeneration · doi:10.1186/s13024-017-0188-6 · Cited by 151 · see citing works
P2RX7 inhibitor suppresses exosome secretion and disease phenotype in P301S tau transgenic mice
Ruan, Z., Delpech, J.-C., Venkatesan Kalavai, S., Van Enoo, A. A., Hu, J., Ikezu, S., & Ikezu, T. (2020) · Molecular Neurodegeneration · doi:10.1186/s13024-020-00396-2 · Cited by 150 · see citing works
Self-citationAlzheimer's Disease: The Role of Microglia in Brain Homeostasis and Proteopathy
Clayton, K. A., Enoo, A. A. V., & Ikezu, T. (2017) · Frontiers in Neuroscience · doi:10.3389/fnins.2017.00680 · Cited by 132 · see citing works
Self-citationMicroglia in Infectious Diseases of the Central Nervous System
Mariani, M. M., & Kielian, T. (2009) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-009-9170-6 · Cited by 127 · see citing works
Partial reduction of microglia does not affect tau pathology in aged mice
Bennett, R. E., Bryant, A., Hu, M., Robbins, A. B., Hopp, S. C., & Hyman, B. T. (2018) · Journal of Neuroinflammation · doi:10.1186/s12974-018-1348-5 · Cited by 91 · see citing works
Åkerblom, M., Sachdeva, R., Quintino, L., Wettergren, E. E., Chapman, K. Z., Manfre, G., Lindvall, O., Lundberg, C., & Jakobsson, J. (2013) · Nature Communications · doi:10.1038/ncomms2801 · Cited by 86 · see citing works
Muraoka, S., Lin, W., Chen, M., Hersh, S. W., Emili, A., Xia, W., & Ikezu, T. (2020) · Methods · doi:10.1016/j.ymeth.2020.02.002 · Cited by 69 · see citing works
Self-citationSpread of pathological tau proteins through communicating neurons in human Alzheimer’s diseasePreprint
Vogel, J. W., Iturria‐Medina, Y., Strandberg, O. T., Smith, R. A., Evans, A. C., Hansson, O., & for the Alzheimer’s Disease Neuroimaging Initiative, A. T. S. B. S. (2019) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/555821 · Cited by 59 · see citing works
Tsutsumi, R., Hori, Y., Seki, T., Kurauchi, Y., Sato, M., Oshima, M., Hisatsune, A., & Katsuki, H. (2019) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2019.02.076 · Cited by 57 · see citing works
Son, Y., Jeong, Y. J., Shin, N., Oh, S. J., Nam, K. R., Choi, H., Choi, J. Y., & Lee, H. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21155553 · Cited by 52 · see citing works
Jüttner, J., Szabó, A., Gross-Scherf, B., et al. (2018) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/434720 · Cited by 26 · see citing works
Nelson, E. J. R., Tuschong, L. M., Hunter, M. J., Bauer, T. R., Burkholder, T. H., & Hickstein, D. D. (2010) · Gene Therapy · doi:10.1038/gt.2010.7 · Cited by 25 · see citing works
Zhu, K., Pieber, M., Han, J., Blomgren, K., Zhang, X., Harris, R. A., & Lund, H. (2020) · Glia · doi:10.1002/glia.23794 · Cited by 15 · see citing works
Exosome Release Promotes Inflammatory Resolution in Activated and Aged MicrogliaPreprint
Udeochu, J. C., Sanchez-Diaz, C., Cai, A., Jovicic, A., & Villeda, S. (2018) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/423558 · Cited by 8 · see citing works
[Clinical signs of occlusion of the cerebral median artery].
Radijicić, B., Nikolić, M., & Lukić (1966) · PubMed · Cited by 1 · see citing works
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Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets
Gao, C., Jiang, J., Tan, Y., & Chen, S. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01588-0 · Cited by 1,616 · see citing works
Synaptic degeneration in Alzheimer disease
Tzioras, M., McGeachan, R. I., Durrant, C. S., & Spires-Jones, T. L. (2023) · Nature Reviews Neurology · doi:10.1038/s41582-022-00749-z · Cited by 504 · see citing works
The effects of microglia-associated neuroinflammation on Alzheimer’s disease
Wang, C., Zong, S., Cui, X., Wang, X., Wu, S., Wang, L., Liu, Y., & Lu, Z. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1117172 · Cited by 318 · see citing works
The neuroimmune axis of Alzheimer’s disease
Jorfi, M., Maaser‐Hecker, A., & Tanzi, R. E. (2023) · Genome Medicine · doi:10.1186/s13073-023-01155-w · Cited by 299 · see citing works
The Contribution of Microglia to Neuroinflammation in Parkinson’s Disease
Badanjak, K., Fixemer, S., Smajić, S., Skupin, A., & Grünewald, A. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22094676 · Cited by 281 · see citing works
Cellular and pathological heterogeneity of primary tauopathies
Chung, D. C., Roemer, S. F., Petrucelli, L., & Dickson, D. W. (2021) · Molecular Neurodegeneration · doi:10.1186/s13024-021-00476-x · Cited by 219 · see citing works
Microglia and monocytes in inflammatory CNS disease: integrating phenotype and function
Spiteri, A. G., Wishart, C. L., Pamphlett, R., Locatelli, G., & King, N. J. C. (2022) · Acta Neuropathologica · doi:10.1007/s00401-021-02384-2 · Cited by 216 · see citing works
“Intriguingly, microglia were shown to be three times as phagocytic and three times more likely to release tau-containing extracellular vesicles when situated near amyloid plaques [61].”
BackgroundMethodInfluentialCell type‐specific roles of APOE4 in Alzheimer disease
Blumenfeld, J., Yip, O., Kim, M. J., & Huang, Y. (2024) · Nature Reviews Neuroscience · doi:10.1038/s41583-023-00776-9 · Cited by 202 · see citing works
Leng, L., Yuan, Z., Pan, R., Su, X., Wang, H., Xue, J., Zhuang, K., Gao, J., Chen, Z., Lin, H. Z., et al. (2022) · Nature Metabolism · doi:10.1038/s42255-022-00643-4 · Cited by 193 · see citing works
Lau, V. Z., Ramer, L. M., & Tremblay, M. (2023) · Nature Communications · doi:10.1038/s41467-023-37304-3 · Cited by 168 · see citing works
Microglia in Alzheimer’s Disease: A Target for Therapeutic Intervention
Zhang, G., Wang, Z., Hu, H., Zhao, M., & Sun, L. (2021) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2021.749587 · Cited by 132 · see citing works
Zhou, T. G., Li, Y., Li, X., Zeng, F., Rao, Y., He, Y., Wang, Y., Liu, M., Li, D., Xu, Z., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-33932-3 · Cited by 122 · see citing works
Baligács, N., Albertini, G., Borrie, S. C., Serneels, L., Pridans, C., Balusu, S., & De Strooper, B. (2024) · Nature Communications · doi:10.1038/s41467-024-54779-w · Cited by 123 · see citing works
Cohn, W., Melnik, M., Huang, C., Teter, B., Chandra, S., Zhu, C., McIntire, L. B., John, V., Gylys, K. H., & Bilousova, T. V. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.766082 · Cited by 120 · see citing works
Yin, Z., Herron, S., Silveira, S., Kleemann, K., Gauthier, C., Mallah, D., Cheng, Y., Margeta, M. A., Pitts, K. M., Barry, J.-L., et al. (2023) · Nature Neuroscience · doi:10.1038/s41593-023-01355-y · Cited by 120 · see citing works
Self-citationMicroglia-Astrocyte Communication in Alzheimer’s Disease
Wu, Y., & Eisel, U. L. M. (2023) · Journal of Alzheimer s Disease · doi:10.3233/jad-230199 · Cited by 118 · see citing works
The role of the immune system in Alzheimer’s disease
Wu, K., Zhang, Y.-R., Huang, Y., Dong, Q., Tan, L., & Yu, J. (2021) · Ageing Research Reviews · doi:10.1016/j.arr.2021.101409 · Cited by 116 · see citing works
Tau filaments are tethered within brain extracellular vesicles in Alzheimer’s disease
Fowler, S. L., Behr, T. S., Turkes, E., O'Brien, D. P., Cauhy, P. M., Rawlinson, I., Edmonds, M. J., Foiani, M. S., Schaler, A. W., Crowley, G., et al. (2024) · Nature Neuroscience · doi:10.1038/s41593-024-01801-5 · Cited by 116 · see citing works
Insights Into the Role of CSF1R in the Central Nervous System and Neurological Disorders
Hu, B., Duan, S., Wang, Z., Li, X., Zhou, Y., Zhang, X., Zhang, Y., Xu, H., & Zheng, H. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.789834 · Cited by 105 · see citing works
Exosome: A novel neurotransmission modulator or non-canonical neurotransmitter?
Xia, X., Wang, Y., Qin, Y., Zhao, S., & Zheng, J. (2022) · Ageing Research Reviews · doi:10.1016/j.arr.2021.101558 · Cited by 101 · see citing works
Tau in neurodegenerative diseases: molecular mechanisms, biomarkers, and therapeutic strategies
Zhang, X., Wang, J., Zhang, Z., & Ye, K. (2024) · Translational Neurodegeneration · doi:10.1186/s40035-024-00429-6 · Cited by 106 · see citing works
Benítez, D. P., Jiang, S., Wood, J. I., Wang, R., Hall, C. M., Peerboom, C., Wong, N. S. M., Stringer, K. M., Vitanova, K. S., Smith, V. C., et al. (2021) · Molecular Neurodegeneration · doi:10.1186/s13024-021-00457-0 · Cited by 79 · see citing works
Self-citationDifferent phenotypes of microglia in animal models of Alzheimer disease
Wei, Y., & Li, X. (2022) · Immunity & Ageing · doi:10.1186/s12979-022-00300-0 · Cited by 71 · see citing works
St‐Pierre, M., Carrier, M., Ibáñez, F. G., Šimončičová, E., Wallman, M., Vallières, L., Parent, M., & Tremblay, M. (2022) · Journal of Neuroinflammation · doi:10.1186/s12974-022-02595-8 · Cited by 76 · see citing works
A critical appraisal of tau‐targeting therapies for primary and secondary tauopathies
Imbimbo, B. P., Ippati, S., Watling, M., & Balducci, C. (2021) · Alzheimer s & Dementia · doi:10.1002/alz.12453 · Cited by 72 · see citing works
Wang, W., Li, Y., Ma, F., Sheng, X., Chen, K., Zhuo, R., Wang, C., Zheng, H., Zhang, Y.-W., Bu, G., et al. (2023) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2023.07.011 · Cited by 71 · see citing works
Microglia, Trem2, and Neurodegeneration
Shi, Q., Gutierrez, R. A., & Bhat, M. A. (2025) · The Neuroscientist · doi:10.1177/10738584241254118 · Cited by 69 · see citing works
“…of a unique microglial subtype in neurodegenerative diseases, termed disease-associated microglia (DAM) (Deczkowska and others 2018) or microglial neurodegenerative (MGnD) phenotype (Clayton and others 2021; Krasemann and others 2017), has been a significant development in the microglia field.”
Madhu, L. N., Kodali, M., Upadhya, R., Rao, S., Somayaji, Y., Attaluri, S., Shuai, B., Kirmani, M., Gupta, S., Maness, N., et al. (2024) · Journal of Extracellular Vesicles · doi:10.1002/jev2.12519 · Cited by 68 · see citing works
Microglia: Friend and foe in tauopathy
Odfalk, K. F., Bieniek, K. F., & Hopp, S. C. (2022) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2022.102306 · Cited by 60 · see citing works
Research progress on the role of extracellular vesicles in neurodegenerative diseases
Li, Z., Wang, X., Wang, X., Yi, X., Wong, Y. K., Wu, J., Xie, F., Hu, D., Wang, Q., Wang, J., et al. (2023) · Translational Neurodegeneration · doi:10.1186/s40035-023-00375-9 · Cited by 65 · see citing works
The Yin and Yang of Microglia-Derived Extracellular Vesicles in CNS Injury and Diseases
Ghosh, M., & Pearse, D. D. (2024) · Cells · doi:10.3390/cells13221834 · Cited by 65 · see citing works
Gong, Z., Cheng, C., Sun, C., & Cheng, X. (2025) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-025-03403-w · Cited by 64 · see citing works
Glotfelty, E. J., Tovar‐y‐Romo, L. B., Hsueh, S., Tweedie, D., Li, Y., Harvey, B. K., Hoffer, B. J., Karlsson, T. E., Olson, L., & Greig, N. H. (2023) · Cells · doi:10.3390/cells12101367 · Cited by 63 · see citing works
Passive immunotherapy for Alzheimer's disease
Guo, X., Li, Y., Zhang, D., & Zhao, Y. (2024) · Ageing Research Reviews · doi:10.1016/j.arr.2024.102192 · Cited by 66 · see citing works
Muraoka, S., Jedrychowski, M. P., Iwahara, N., Abdullah, M., Onos, K. D., Keezer, K. J., Hu, J., Ikezu, S., Howell, G. R., Gygi, S. P., et al. (2021) · Journal of Proteome Research · doi:10.1021/acs.jproteome.0c00934 · Cited by 61 · see citing works
Self-citationMicroglial Extracellular Vesicles as Vehicles for Neurodegeneration Spreading
Aires, I. D., Ribeiro‐Rodrigues, T., Boia, R., Ferreira-Rodrigues, M., Girão, H., Ambrósio, A. F., & Santiago, A. R. (2021) · Biomolecules · doi:10.3390/biom11060770 · Cited by 56 · see citing works
Gomes, P., Tzouanou, F., Skolariki, K., Vamvaka-Iakovou, A., Nogueras‐Ortiz, C. J., Tsirtsaki, K., Waites, C. L., Vlamos, P., Sousa, N., Costa‐Silva, B., et al. (2022) · Experimental Neurology · doi:10.1016/j.expneurol.2022.114183 · Cited by 57 · see citing works
Wang, L., Zhang, X., Yang, Z., Wang, B., Gong, H., Zhang, K., Lin, Y., & Sun, M. (2024) · Translational Neurodegeneration · doi:10.1186/s40035-024-00453-6 · Cited by 55 · see citing works
Extracellular vesicles: New horizons in neurodegeneration
Chen, J., Tian, C., Xiong, X., Yang, Y., & Zhang, J. (2025) · eBioMedicine · doi:10.1016/j.ebiom.2025.105605 · Cited by 53 · see citing works
Beyond Amyloid and Tau: The Critical Role of Microglia in Alzheimer’s Disease Therapeutics
Dias, D., & Socodato, R. (2025) · Biomedicines · doi:10.3390/biomedicines13020279 · Cited by 57 · see citing works
Wang, Q., Lu, M., Zhu, X., Gu, X., Zhang, T., Xia, C., Yang, L., Xu, Y., & Zhou, M. (2022) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2022.113412 · Cited by 52 · see citing works
Extracellular vesicles: translational research and applications in neurology
Manolopoulos, A., Yao, P. J., & Kapogiannis, D. (2025) · Nature Reviews Neurology · doi:10.1038/s41582-025-01080-z · Cited by 55 · see citing works
Neuroprotective and Neurotoxic Effects of Glial-Derived Exosomes
Oyarce, K., Cepeda, M. Y., Lagos, R., Garrido, C., Vega-Letter, A. M., García, M. D. L. Á., Luz‐Crawford, P., & Elizondo-Vega, R. J. (2022) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2022.920686 · Cited by 53 · see citing works
Harnessing human iPSC-microglia for CNS-wide delivery of disease-modifying proteins
Chadarevian, J. P., Davtyan, H., Chadarevian, A. L., Nguyen, J., Capocchi, J. K., Le, L., Escobar, A., Chadarevian, T., Mansour, K., Deynega, E., et al. (2025) · Cell stem cell · doi:10.1016/j.stem.2025.03.009 · Cited by 53 · see citing works
The multiple faces of extracellular vesicles released by microglia: Where are we 10 years after?
Gabrielli, M., Raffaele, S., Fumagalli, M., & Verderio, C. (2022) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2022.984690 · Cited by 50 · see citing works
Walker, J. M., Orr, M. E., Orr, T. C., Thorn, E. L., Christie, T. D., Yokoda, R. T., Vij, M., Ehrenberg, A. J., Marx, G. A., McKenzie, A. T., et al. (2023) · Alzheimer s & Dementia · doi:10.1002/alz.13484 · Cited by 47 · see citing works
Natale, F., Fusco, S., & Grassi, C. (2022) · Translational Neurodegeneration · doi:10.1186/s40035-022-00326-w · Cited by 48 · see citing works
Fetal brain response to maternal inflammation requires microglia
Lessi, M., Iturza, N. D., Stogsdill, J., Faits, T., Kim, K., Levin, J. Z., & Arlotta, P. (2024) · Development · doi:10.1242/dev.202252 · Cited by 46 · see citing works
Delpech, J.-C., Pathak, D., Varghese, M., Kalavai, S. V., Hays, E. C., Hof, P. R., Johnson, W. E., Ikezu, S., Medalla, M., Luebke, J. I., et al. (2021) · Science Translational Medicine · doi:10.1126/scitranslmed.abe8455 · Cited by 45 · see citing works
Self-citationGranzyme K+ CD8 T cells slow tauopathy progression by targeting microglia
Mason, H. D., Latour, Y. L., Boughter, C. T., Johnson, K. R., Maric, D., Dorrier, C., Guedes, V. A., Lai, C., Duncker, P. C., Johnson, A. M., et al. (2025) · Nature Immunology · doi:10.1038/s41590-025-02198-4 · Cited by 44 · see citing works
Extracellular vesicles in Alzheimer’s disease: from pathology to therapeutic approaches
Thakor, A., & Garcia-Contreras, M. (2023) · Neural Regeneration Research · doi:10.4103/1673-5374.343882 · Cited by 41 · see citing works
Gao, C., Shen, X., Tan, Y., & Chen, S. (2022) · Journal of Neuroinflammation · doi:10.1186/s12974-022-02580-1 · Cited by 43 · see citing works
Brain incoming call from glia during neuroinflammation: Roles of extracellular vesicles
D’Egidio, F., Castelli, V., d’Angelo, M., Ammannito, F., Quintiliani, M., & Cimini, A. (2024) · Neurobiology of Disease · doi:10.1016/j.nbd.2024.106663 · Cited by 39 · see citing works
Synapses, Microglia, and Lipids in Alzheimer’s Disease
Paasila, P. J., Aramideh, J. A., Sutherland, G. T., & Graeber, M. B. (2022) · Frontiers in Neuroscience · doi:10.3389/fnins.2021.778822 · Cited by 38 · see citing works
Hirota, Y., Sakakibara, Y., Ibaraki, K., Takei, K., Iijima, K., & Sekiya, M. (2022) · Brain Communications · doi:10.1093/braincomms/fcac286 · Cited by 39 · see citing works
Extracellular Vesicle-Mediated Neuron–Glia Communications in the Central Nervous System
Ikezu, T., Yang, Y., Verderio, C., & Krämer‐Albers, E. (2024) · Journal of Neuroscience · doi:10.1523/jneurosci.1170-24.2024 · Cited by 43 · see citing works
Self-citationKloske, C. M., Dugan, A. J., Weekman, E. M., Winder, Z., Patel, E., Nelson, P. T., Fardo, D. W., & Wilcock, D. M. (2021) · Journal of Neuropathology & Experimental Neurology · doi:10.1093/jnen/nlab085 · Cited by 36 · see citing works
Visconte, C., Golia, M. T., Fenoglio, C., Serpente, M., Gabrielli, M., Arcaro, M., Sorrentino, F., Busnelli, M., Arighi, A., Fumagalli, G., et al. (2023) · GeroScience · doi:10.1007/s11357-023-00746-0 · Cited by 36 · see citing works
Neurodegenerative fluid biomarkers are enriched in human cervical lymph nodes
Al‐Diwani, A., Provine, N. M., Murchison, A. G., Laban, R., Swann, O., Koychev, I. G., Sheerin, F., Mesquita, S. D., Heslegrave, A., Zetterberg, H., et al. (2024) · Brain · doi:10.1093/brain/awae329 · Cited by 35 · see citing works
Neuroinflammation in Age-Related Neurodegenerative Diseases: Role of Mitochondrial Oxidative Stress
Abadin, X., de Dios, C., Zubillaga, M., Ivars, E., Puigròs, M., Marı́, M., Morales, A., Vizuete, M., Vitórica, J., Trullás, R., et al. (2024) · Antioxidants · doi:10.3390/antiox13121440 · Cited by 35 · see citing works
Tau Seeding Mouse Models with Patient Brain-Derived Aggregates
Robert, A., Schöll, M., & Vogels, T. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22116132 · Cited by 35 · see citing works
Gutiérrez‐Fernández, M., de la Cuesta, F., Tallón, A., Puertas, I., Fernández-Fournier, M., Laso-García, F., Frutos, M. C. G.-D., Díez‐Tejedor, E., & Otero‐Ortega, L. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22169011 · Cited by 33 · see citing works
Role of Glia-Derived Extracellular Vesicles in Neurodegenerative Diseases
Li, T., Tan, X., Li, S., Al-Nusaif, M., & Le, W. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.765395 · Cited by 33 · see citing works
Congdon, E. E., Pan, R., Jiang, Y., Sandusky‐Beltran, L. A., Dodge, A., Lin, Y., Liu, M., Kuo, M., Kong, X., & Sigurdsson, E. M. (2022) · EBioMedicine · doi:10.1016/j.ebiom.2022.104249 · Cited by 32 · see citing works
You, Y., Chen, M., Tang, Y., Yu, W.-X., Pang, X., Chu, Y., Zhang, H., Shang, K., Deng, G., Zhou, L., et al. (2023) · Journal of Neuroinflammation · doi:10.1186/s12974-023-02772-3 · Cited by 32 · see citing works
A small-molecule TLR4 antagonist reduced neuroinflammation in female E4FAD mice
Balu, D., Valencia‐Olvera, A. C., Nguyen, A. Q., Patnam, M., York, J. M., Peri, F., Neumann, F., LaDu, M. J., & Tai, L. M. (2023) · Alzheimer s Research & Therapy · doi:10.1186/s13195-023-01330-6 · Cited by 32 · see citing works
Yang, Y. H., Ishima, T., Wan, X., Wei, Y., Chang, L., Zhang, J., Qu, Y., & Hashimoto, K. (2021) · European Archives of Psychiatry and Clinical Neuroscience · doi:10.1007/s00406-021-01325-0 · Cited by 32 · see citing works
A novel molecular class that recruits HDAC/MECP2 complexes to PU.1 motifs reduces neuroinflammation
Ralvenius, W. T., Mungenast, A. E., Woolf, H., Huston, M. M., Gillingham, T. Z., Godin, S. K., Penney, J., Cam, H. P., Gao, F., Fernandez, C. G., et al. (2023) · Journal of Experimental Medicine · doi:10.1084/jem.20222105 · Cited by 31 · see citing works
“Amyloid-β – associated microglia were shown to secrete extracellular vesicles that contain phosphorylated tau and their depletion abrogated tau propagation (Clayton et al., 2021).”
Karaahmet, B., Le, L., Mendes, M. S., Majewska, A. K., & O’Banion, M. K. (2022) · Journal of Neuroinflammation · doi:10.1186/s12974-022-02532-9 · Cited by 29 · see citing works
Gut microbiota, pathogenic proteins and neurodegenerative diseases
Wei, W., Wang, S., Xu, C., Zhou, X., Lian, X., He, L., & Li, K. (2022) · Frontiers in Microbiology · doi:10.3389/fmicb.2022.959856 · Cited by 29 · see citing works
Gabrielli, M., Tozzi, F., Verderio, C., & Origlia, N. (2022) · Cells · doi:10.3390/cells12010063 · Cited by 31 · see citing works
Pait, M. C., Kaye, S. D., Su, Y., Kumar, A., Singh, S., Gironda, S. C., Vincent, S., Anwar, M., Carroll, C. M., Snipes, J. A., et al. (2024) · Journal of Extracellular Vesicles · doi:10.1002/jev2.12398 · Cited by 27 · see citing works
Zhuang, X., Jie, L., Song, Y., Ban, R., Zhao, X., Xia, Z., Wang, Z., & Zhang, G. (2024) · NeuroMolecular Medicine · doi:10.1007/s12017-024-08815-z · Cited by 32 · see citing works
Zheng, Q., Yu, Y., Su, Y., Cao, B., Shao, H., & Yang, J. (2023) · Inflammation · doi:10.1007/s10753-023-01875-6 · Cited by 28 · see citing works
Sattarov, R., Havers, M., Orbjörn, C., Stomrud, E., Janelidze, S., Laurell, T., & Mattsson, N. (2024) · Scientific Reports · doi:10.1038/s41598-024-75406-0 · Cited by 27 · see citing works
St‐Pierre, M., VanderZwaag, J., Loewen, S. M., & Tremblay, M. (2022) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2022.932572 · Cited by 27 · see citing works
St‐Pierre, M., Carrier, M., Ibáñez, F. G., Khakpour, M., Wallman, M., Parent, M., & Tremblay, M. (2023) · Journal of Neuroinflammation · doi:10.1186/s12974-023-02752-7 · Cited by 26 · see citing works
Zhang, Q., Yi, Y., Chen, T., Ai, Y., Chen, Z., Liu, G., Tang, Z., Chen, J., Xu, T., Chen, X., et al. (2025) · Journal of Nanobiotechnology · doi:10.1186/s12951-025-03390-2 · Cited by 27 · see citing works
Vaz, M., Martins, T. S., & Henriques, A. G. (2022) · Journal of Neurochemistry · doi:10.1111/jnc.15697 · Cited by 25 · see citing works
Auger, A., Faidi, R., Rickman, A. D., Peña-Martinez, C., Fajfer, A., Carling, J., Hilyard, A., Ali, M., Ono, R., Cleveland, C., et al. (2025) · npj Dementia · doi:10.1038/s44400-025-00011-5 · Cited by 29 · see citing works
Hemonnot-Girard, A.-L., Meersseman, C., Pastore, M., Garcia, V., Linck, N., Rey, C., Chebbi, A., Jeanneteau, F., Ginsberg, S. D., Lachuer, J., et al. (2022) · Journal of Neuroinflammation · doi:10.1186/s12974-022-02581-0 · Cited by 24 · see citing works
Integrating amyloid and tau imaging with proteomics and genomics in Alzheimer’s disease
Vilkaite, G., Vogel, J. W., & Mattsson, N. (2024) · Cell Reports Medicine · doi:10.1016/j.xcrm.2024.101735 · Cited by 25 · see citing works
Microglia internalize tau monomers and fibrils using distinct receptors but similar mechanisms
Falkon, K. F., Danford, L., Kuri, E. G., Esquinca‐Moreno, P., Señeriz, Y. L. P., Smith, S. A., Wickline, J. L., Louwrier, A., McPhail, J. A., Sayre, N. L., et al. (2024) · Alzheimer s & Dementia · doi:10.1002/alz.14418 · Cited by 25 · see citing works
Emerging Roles of Cells and Molecules of Innate Immunity in Alzheimer’s Disease
Tamburini, B., Badami, G. D., Manna, M. P. L., Azgomi, M. S., Caccamo, N., & Dieli, F. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241511922 · Cited by 22 · see citing works
Repurposing of pexidartinib for microglia depletion and renewal
Weyer, M.-P., Strehle, J., Schäfer, M. K. E., & Tegeder, I. (2023) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2023.108565 · Cited by 23 · see citing works
Takatori, S., Kondo, M., & Tomita, T. (2025) · Inflammation and Regeneration · doi:10.1186/s41232-025-00383-4 · Cited by 23 · see citing works
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Fan, H., Zhang, M., Wen, J., Wang, S., Yuan, M., Sun, H., Shu, L., Xu, Y., Pu, Y., & Cai, Z. (2023) · Journal of Biomedical Research · doi:10.7555/jbr.37.20220220 · Cited by 22 · see citing works
Herron, S., Delpech, J.-C., Madore, C., & Ikezu, T. (2022) · STAR Protocols · doi:10.1016/j.xpro.2022.101670 · Cited by 21 · see citing works
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Song, X., Zhou, H.-Y., Sun, Y.-Y., & Huang, H. (2021) · Journal of Alzheimer s Disease · doi:10.3233/jad-210337 · Cited by 20 · see citing works
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Yeo, S., Jang, J., Jung, H. J., Lee, H., & Choe, Y. (2023) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2023.1250335 · Cited by 18 · see citing works
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Joo, H. S., Jeon, H. Y., Hong, E. B., Kim, H.-Y., & Lee, J. M. (2023) · Current Opinion in Psychiatry · doi:10.1097/yco.0000000000000842 · Cited by 18 · see citing works
Singhaarachchi, P. H., Antal, P., Calon, F., Culmsee, C., Delpech, J.-C., Feldotto, M., Geertsema, J., Hoeksema, E. E., Kőrösi, A., Layé, S., et al. (2024) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2024.105724 · Cited by 18 · see citing works
Self-citationGao, R., Gao, Y., Su, W., & Wang, R. (2025) · Aging and Disease · doi:10.14336/ad.2024.1629 · Cited by 18 · see citing works
Monitoring neurodegeneration through brain-derived extracellular vesicles in biofluids
Torrini, F., Gil-García, M., Cardellini, J., Frigerio, R., Basso, M., Gori, A., & Arosio, P. (2025) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2025.03.006 · Cited by 17 · see citing works
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Son, G., Steinbusch, H. W. M., López‐Iglesias, C., Moon, C., & Jahanshahi, A. (2021) · Brain Pathology · doi:10.1111/bpa.13033 · Cited by 16 · see citing works
- Authors
- Clayton, K., Delpech, J. C., Herron, S., Iwahara, N., Ericsson, M., Saito, T., Saido, T. C., Ikezu, S., & Ikezu, T.
- Affiliations
- Boston University (US)
- Harvard University (US)
- RIKEN Center for Brain Science (JP)
- Corresponding author
- Ikezu, Tsuneya
- ORCID
- Venue
- Molecular Neurodegeneration
- Published
- 2021-03-22
- Volume
- 16
- Issue
- 1
- Pages
- 18-18
- ISSN
- 1750-1326 (ISSN-L)
- PMC
- PMC7986521
- OpenAlex
- W3137321433
- Cited by
- 245
- References
- 73
- Citations by year
- 2026: 35 · 2025: 42 · 2024: 49 · 2023: 43 · 2022: 49 · 2021: 26 · 2013: 1
- FWCI
- 26.24
- Type
- journal article
- Language
- en
- Update notices
- correction (2021-04-14)
- Open access
- gold
- doi.org
- Locations
- Molecular Neurodegeneration (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- HAL (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- OpenBU (Boston University) (submittedVersion)
- Oskar-Bordeaux (Universite de Bordeaux) (submittedVersion, cc-by)
- Funders
- Alzheimer's Association (DVT-14-320835)
- BrightFocus Foundation (A2016551S)
- Cure Alzheimer's Fund (N/A)
- National Institute on Aging (R01 AG066429, RF1 AG054199, R56 AG057469, P30 AG0138423, F31 AG057170)
- NIGMS (T32 GM008541)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
- Keywords
- microglia, extracellular vesicles, tau propagation, Alzheimer's disease, amyloid plaques, PLX5622, CSF1R inhibition, microglial depletion, CD9, TSG101, medial entorhinal cortex, dentate gyrus, dystrophic neurites, tau phosphorylation, plaque-associated microglia, disease progression
- MeSH terms
- Extracellular Vesicles, Animals, Female, Genetic Vectors, Humans, Injections, Male, Mice, Inbred C57BL, Organic Chemicals, Recombinant Proteins, Receptors, Granulocyte-Macrophage Colony-Stimulating Factor, Neurites, Amyloid beta-Protein Precursor, tau Proteins, Point Mutation, Microglia, Entorhinal Cortex, Dentate Gyrus, Mutation, Missense, Mice, Gene Knock-In Techniques, Plaque, Amyloid, Protein Aggregation, Pathological
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