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Innate immune memory in the brain shapes neurological disease hallmarks
Open accessAbstract
Innate immune memory is a vital mechanism of myeloid cell plasticity that occurs in response to environmental stimuli and alters subsequent immune responses. Two types of immunological imprinting can be distinguished-training and tolerance. These are epigenetically mediated and enhance or suppress subsequent inflammation, respectively. Whether immune memory occurs in tissue-resident macrophages in vivo and how it may affect pathology remains largely unknown. Here we demonstrate that peripherally applied inflammatory stimuli induce acute immune training and tolerance in the brain and lead to differential epigenetic reprogramming of brain-resident macrophages (microglia) that persists for at least six months. Strikingly, in a mouse model of Alzheimer's pathology, immune training exacerbates cerebral β-amyloidosis and immune tolerance alleviates it; similarly, peripheral immune stimulation modifies pathological features after stroke. Our results identify immune memory in the brain as an important modifier of neuropathology.
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“Next we tested the effect of Aβ42 and LPS on oxidative stress response in microglial cells as amyloid and inflammation trigger and exacerbate pathological changes in AD brain (Wendeln et al., 2018).”
From Alzheimer's-associated PU.1 expression levels regulate microglial inflammatory response (2021) · cites this paper as Wendeln et al., 2018
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“peripheral insults that cause a systemic inflammatory response might affect ongoing inflammation in the CNS mainly by microglial activation, production of inflammatory molecules, as well as recruitment of peripheral immune cells into the brain, thus shaping a cerebral inflammatory milieu that may seriously affect neuronal function (50, 52, 53).”
From The Role of Short-Chain Fatty Acids From Gut Microbiota in Gut-Brain Communication (2020) · cites this paper as [53]
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“However, nonspecific microglia activation induced by lipopolysaccharide does not have the same amyloid-promoting effect as myelin dysfunction, as increases, decreases or no changes in amyloid burden have been reported48–51.”
From Myelin dysfunction drives amyloid-β deposition in models of Alzheimer’s disease (2023) · cites this paper as [49]
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“A Hif1a epigenetic and transcriptomic signature was recently identified in microglia following immune training by peripheral LPS administration in APP/PS1 mice65.”
From Transcriptional signature in microglia associated with Aβ plaque phagocytosis (2021) · cites this paper as [65]
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“Animal and in-vitro studies demonstrate that inflammatory stimuli may initiate long-term priming of the microglia, peripheral CD4+ and CD8+ T cells to a proinflammatory state, (352-354) potentially increasing amyloid plaque deposition.(355)”
From Dementia prevention, intervention, and care: 2024 report of the Lancet standing Commission (2024) · cites this paper as [355]
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“Our data suggest that PU.1 may contribute to this mechanism of innate immune memory in the brain (Wendeln et al., 2018).”
From Alzheimer's-associated PU.1 expression levels regulate microglial inflammatory response (2021) · cites this paper as Wendeln et al., 2018
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In the citing paper
“although it is important to note that the efficiency of individual phagocytic processes can be dependent on experimental conditions65–67.”
From Transcriptional signature in microglia associated with Aβ plaque phagocytosis (2021) · cites this paper as [65]
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“We found little overlap between the Hif1a module reported in65 and the Hif1a regulon identified here (Supplementary Fig. 13d)”
From Transcriptional signature in microglia associated with Aβ plaque phagocytosis (2021) · cites this paper as [65]
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“In healthy mice, peripherally applied LPS can differentially reprogram the epigenome of microglia by inducing either acute immune training or tolerance pending upon the number of injections [102].”
From What would it take to prove that a chronic infection is a causal agent in Alzheimer’s disease? (2025) · cites this paper as [102]
In the citing paper
“and systemic endotoxin precipitates brain pathology in mice expressing prions [74], APP variants [33] or TAU variants [69] or mice with α-synuclein injected in the brain [46].”
From The endotoxin hypothesis of neurodegeneration (2019) · cites this paper as [33]
In the citing paper
“Microglial markers such as purinergic receptor P2Y G-protein coupled 12 (P2ryl2), transmembrane protein 119 (Tmem119), and Fc receptor-like S, scavenger receptor (Fcrls), are used to define microglia homeostatic state.”
From Transcriptional and Epigenetic Regulation of Microglia in Health and Disease (2019) · cites this paper as [11]
In the citing paper
“Whereas, inflammatory marker Clec7a is used to define microglia in neurodegenerative state [11].”
From Transcriptional and Epigenetic Regulation of Microglia in Health and Disease (2019) · cites this paper as [11]
In the citing paper
“Immune memory in microglia and macrophages are shaped by epigenetically mediated alterations in the enhancer repertoire of targeted genes [11, 32].”
From Transcriptional and Epigenetic Regulation of Microglia in Health and Disease (2019) · cites this paper as [11]
In the citing paper
“In addition, APP mice with four-time LPS treatment showed increased H3K4me1 levels in putative enhancers related to phagocytic function [11].”
From Transcriptional and Epigenetic Regulation of Microglia in Health and Disease (2019) · cites this paper as [11]
In the citing paper
“Cerebral beta-amyloidosis activates HIF-1a and mTOR pathways, which leads to transcriptional and functional alterations associated with increased inflammatory and immune response genes in MGnD [11].”
From Transcriptional and Epigenetic Regulation of Microglia in Health and Disease (2019) · cites this paper as [11]
In the citing paper
“Peripheral immune stimulation and cerebral beta-amyloidosis can lead to epigenetic modification in microglia.”
From Transcriptional and Epigenetic Regulation of Microglia in Health and Disease (2019) · cites this paper as [11]
In the citing paper
“These data suggest the differential effect of immune training versus tolerance due to multiple peripheral immune stimulation, which is reflected in the epigenetic landscape of MGnD in AD mouse models.”
From Transcriptional and Epigenetic Regulation of Microglia in Health and Disease (2019) · cites this paper as [11]
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“Therefore, a more intriguing example about the modulation of innate immunity memory comes from the recent report on the microglia memory in Alzheimer’s disease (1).”
BackgroundInfluentialAlterations in Chromatin Structure and Function in the Microglia
Fujita, Y., & Yamashita, T. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.626541 · Cited by 22
“…regulate early wiring, synaptic pruning and formation, and cell death and survival, which are indispensable for establishing and maintaining neural circuits (Ransohoff and El Khoury, 2015; Schafer and Stevens, 2015; Hong et al., 2016; Tay et al., 2017; Thion and Garel, 2017; Wolf et al., 2017).”
BackgroundImmune Response at the Crossroads of Atherosclerosis and Alzheimer's Disease
Stahr, N. A., & Galkina, E. (2022) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2022.870144 · Cited by 18
Nonoguchi, H. A., Kouo, T. W. S., Kortagere, S., Hillman, J., Boyle, D. L., & Mandyam, C. D. (2022) · Brain Sciences · doi:10.3390/brainsci12080972 · Cited by 18
“We add to the published findings in mice on increased expression of the pro-inflammatory cytokines TNFα, IL-1β, IL-6 in the periphery 4–7 h post-LPS treatment in both sexes [6,9,11,28], to show that this increase is evident in rats 24 h after LPS exposure.”
BackgroundMethodInfluentialAno, Y., Ohya, R., Kondô, K., & Nakayama, H. (2019) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2019.00016 · Cited by 19
“In aged mice, microglial inflammation is induced by Aβ and other antigens; activated microglia produce pro-inflammatory cytokines and reactive oxygen species, both of which lead to cognitive impairment (Sarlus and Heneka, 2017; Wendeln et al., 2018).”
BackgroundHuman Monocytes Plasticity in Neurodegeneration
Savinetti, I., Papagna, A., & Foti, M. (2021) · Biomedicines · doi:10.3390/biomedicines9070717 · Cited by 19
“Peripheral inflammatory stimuli leading to long-lasting training of microglia which exacerbates CNS β-amyloidosis in a mouse model of Alzheimer disease have been demonstrated [66].”
BackgroundPiccoli, T., Castro, F., Bella, V. L., Meraviglia, S., Simone, M. D., Salemi, G., Dieli, F., & Spataro, R. (2023) · BMC Neurology · doi:10.1186/s12883-023-03255-x · Cited by 17
Gao, M., Wang, X., Su, S., Feng, W., Lai, Y., Huang, K., Cao, D., & Wang, Q. (2024) · Neural Regeneration Research · doi:10.4103/nrr.nrr-d-23-01595 · Cited by 18
“Wendeln’s study (Wendeln et al., 2018) suggested that, when compared to mice that received only one injection of lipopolysaccharide, mice that received multiple injections of low-dose lipopolysaccharide responded differently to amyloid-β (Aβ) and stroke, indicating a surveillance pathway for…”
Enduring and Sex-specific Changes in Hippocampal Gene Expression after a Subchronic Immune Challenge
Tchessalova, D., & Tronson, N. C. (2020) · Neuroscience · doi:10.1016/j.neuroscience.2019.12.019 · Cited by 18
Shukuri, M., Uchino, M., Sakamaki, T., Onoe, S., Hosoi, R., Todoroki, K., Arano, Y., Sakai, T., Akizawa, H., & Inoue, O. (2021) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2021.11.008 · Cited by 17
Guevara, C. A., Valle, P. D., & Mercedes, C. R. (2020) · Journal of Neuroscience · doi:10.1523/jneurosci.2175-19.2019 · Cited by 17
Grathwohl, S., Quansah, E., Maroof, N., Steiner, J. A., Spycher, L., Benmansour, F., Duran-Pacheco, G., Siebourg-Polster, J., Oroszlan-Szovik, K., Remy, H., et al. (2020) · doi:10.21203/rs.3.rs-100199/v1 · Cited by 17
“effect which can persist for at least six months [80].”
BackgroundTrained immunity in cardiovascular disease
Riksen, N. P., Netea, M. G., Ait‐Oufella, H., Chavakis, T., & Hajishengallis, G. (2025) · European Heart Journal · doi:10.1093/eurheartj/ehaf982 · Cited by 21
Mizobuchi, H., Yamamoto, K., Tsutsui, S., Yamashita, M., Nakata, Y., Inagawa, H., Kohchi, C., & Soma, G. (2020) · Scientific Reports · doi:10.1038/s41598-020-65998-8 · Cited by 18
van Ton, A. M. P., Leijte, G. P., Franssen, G. M., Bruse, N., Booij, J., Doorduin, J., Rijpkema, M., Kox, M., Abdo, W. F., & Pickkers, P. (2021) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2021.04.004 · Cited by 16
“In addition, single peripheral administration of LPS in mice induced immune training, whereas repeated challenges induced immune tolerance (Wendeln et al., 2018).”
BackgroundInfluentialInflammation in the gut is encoded by neurons in the brain
Brea, D., & Veiga‐Fernandes, H. (2022) · Nature · doi:10.1038/d41586-021-03802-x · Cited by 15
Gaviglio, E. A., Ramos, J. M. P., Arroyo, D. S., Bussi, C., Iribarren, P., & Rodriguez‐Galán, M. C. (2022) · International Immunopharmacology · doi:10.1016/j.intimp.2022.108546 · Cited by 18
Shao, S., Zou, Y. Z., Kennedy, K. G., Dimick, M. K., MacIntosh, B. J., & Goldstein, B. I. (2023) · The International Journal of Neuropsychopharmacology · doi:10.1093/ijnp/pyad063 · Cited by 17
“This in turn results in microglial activation, production of inflammatory molecules (Hoogland et al., 2015; Wendeln et al., 2018), and vagal nerve activation, collectively causing neuroinflammation (Breit et al., 2018).”
BackgroundSchirmbeck, G. H., Seady, M., Fróes, F. T., Taday, J., Ré, C. D., Souza, J. M., Gonçalves, C. A., & Leite, M. C. (2023) · NeuroToxicology · doi:10.1016/j.neuro.2023.11.009 · Cited by 18
Alam, K., Nair, L. S., Mukherjee, S., Kaur, K., Singh, M., Kaity, S., Ravichandiran, V., Banerjee, S., & Roy, S. (2024) · Bio-Design and Manufacturing · doi:10.1007/s42242-024-00282-6 · Cited by 16
“The long-term effects on microglial memory remain to be elucidated [14].”
Updating Neuroimmune Targets in Central Nervous System Dysfunction
Valente, L. A., Begg, L. R., & Filiano, A. J. (2019) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2019.04.013 · Cited by 16
Mesenchymal-Stem-Cell–Derived Extracellular Vesicles Mitigate Trained Immunity in the Brain
Feng, Y., Guo, M. A., Zhao, H., Han, S., Dong, Q., & Cui, M. (2020) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2020.599058 · Cited by 16
Trained Microglia Trigger Memory Loss
Lelios, I., & Greter, M. (2018) · Immunity · doi:10.1016/j.immuni.2018.04.033 · Cited by 15
Neuropsychiatric lupus erythematosus: Focusing on autoantibodies
Wang, J., Xu, J., & Yang, P. (2022) · Journal of Autoimmunity · doi:10.1016/j.jaut.2022.102892 · Cited by 16
Petrof, B. J., Podolsky, T., Bhattarai, S., Tan, J., & Ding, J. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1183066 · Cited by 16
“For example, systemic LPS administration induced trained immunity in brain microglial cells that persisted for at least 6 months in mice (55).”
BackgroundInfluentialLiang, N., Harsch, B. A., Zhou, S., Borkowska, A. G., Shearer, G. C., Kaddurah‐Daouk, R., Newman, J. W. I., & Borkowski, K. (2023) · Progress in Lipid Research · doi:10.1016/j.plipres.2023.101265 · Cited by 15
Zhou, L., Wang, N., Feng, W., Liu, X., Wu, Q., Chen, J., Jiao, X., Ning, X., Qi, Z., Xu, Z., et al. (2024) · Glia · doi:10.1002/glia.24606 · Cited by 14
“To further investigate the role of sTGFBR3 in neuroinflammation, we established an acute LPS injection mouse model as previously described (Wendeln et al., 2018).”
InfluentialLang, G.-P., Ndongson‐Dongmo, B., Lajqi, T., Brodhun, M., Han, Y., Wetzker, R., Frasch, M. G., & Bauer, R. (2020) · Journal of Neuroinflammation · doi:10.1186/s12974-020-01954-7 · Cited by 15
Fetal inflammation induces acute immune tolerance in the neonatal rat hippocampus
Singh, G., Segura, B. J., Georgieff, M., & Gisslen, T. A. (2021) · Journal of Neuroinflammation · doi:10.1186/s12974-021-02119-w · Cited by 15
“LPS over four consecutive days have decreasing concentrations of plasma and brain cytokines after each dose, suggesting immune tolerance [28].”
BackgroundOxygen Sensing and Signaling in Alzheimer’s Disease: A Breathtaking Story!
Correia, S. C., & Moreira, P. I. (2021) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-021-01148-6 · Cited by 14
Brackhan, M., Calza, G., Lundgren, K., Bascuñana, P., Brüning, T., Soliymani, R., Kumar, R., Abelein, A., Baumann, M., Lalowski, M. M., et al. (2022) · EMBO Reports · doi:10.15252/embr.202154405 · Cited by 14
“Indeed, a peripheral injection of lipopolysaccharides exacerbated A b pathology in a similar fashion as an i.p. injection of APPtg brain extract in APP23 mice (Wendeln et al , 2018).”
Potential effects of PFAS exposure on trained immunity: From mechanisms to health risks
Qiu, J., Huo, X., Dai, Y., Huang, Y., & Xu, X. (2025) · Ecotoxicology and Environmental Safety · doi:10.1016/j.ecoenv.2025.118757 · Cited by 15
Trained immunity modulators: A new frontier in immunoregulation and disease intervention
Chen, J., Wang, C., Chen, S., Cai, H., Wang, M., Chang, J., Cai, X., Yang, J., & Cao, P. (2025) · Journal of Advanced Research · doi:10.1016/j.jare.2025.09.029 · Cited by 15
“Experimental murine AD models have demonstrated that systemic immune challenges provoke enduring epigenetic reprogramming of central nervous system macrophages (namely microglia), subsequently accelerating cerebral b -amyloid plaque deposition and cognitive decline [76].”
Kurki, S., Ala‐Kurikka, T., Lipponen, A., Pospelov, A. S., Rõlova, T., Koıstınaho, J., Voipio, J., & Kaila, K. (2023) · Journal of Neuroinflammation · doi:10.1186/s12974-023-02851-5 · Cited by 13
Steinberg, N., Galleguillos, D., Zaidi, A. K., Horkey, M., & Sipione, S. (2023) · Journal of Neuroinflammation · doi:10.1186/s12974-023-02963-y · Cited by 14
“Mice were injected intraperitoneally with saline or LPS in sterile saline solution at a daily dose of 0.5 mg per kg body weight, as previously described [51, 57, 58].”
BackgroundMethodResultInfluentialCharoensaensuk, V., Huang, B., Huang, S.-T., Lin, C., Xie, S.-Y., Chen, C., Chen, Y.-C., Cheng, H., Liu, Y.-S., Lai, S., et al. (2024) · Journal of Pharmacological Sciences · doi:10.1016/j.jphs.2024.02.006 · Cited by 15
He, Y., Zhao, J., Ma, Y., Yan, X., Duan, Y., Zhang, X., Dong, H., Fang, R., Zhang, Y., Li, Q., et al. (2024) · Journal of Neuroinflammation · doi:10.1186/s12974-024-03145-0 · Cited by 15
“The concept of immune training has been proposed by previous studies showing that peripherally applied inflammatory stimuli can induce acute immune training in the brain, which effectively acts as an important modifier of neuropathology [64].”
BackgroundLee, H., Lee, Y., Chung, C., Park, S., Shin, H. J., Joe, E.-H., Lee, S. J., Kim, D. W., Jo, S., & Choi, S. (2024) · Glia · doi:10.1002/glia.24629 · Cited by 15
“It has been reported that chemokine levels in plasma decrease following two consecutive days of LPS IP injection, while they significantly increase in the brain (Thomson et al., 2020; Wendeln et al., 2018).”
Zhang, H., Bi, F., Zhao, P., Cui, H., Tao, X., Zhang, J., Li, C., Cao, Y., Wang, N., & Li, H. (2025) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2025.119464 · Cited by 15
In situ vaccination at a peripheral tumor site augments response against melanoma brain metastases
Clark, P. A., Sriramaneni, R. N., Jin, W. J., Jagodinsky, J. C., Bates, A. M., Jaquish, A. A., Anderson, B. R., Le, T. Q. H., Lubin, J. A., Chakravarty, I., et al. (2020) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2020-000809 · Cited by 13
Kurakin, A. V., & Bredesen, D. E. (2020) · Aging · doi:10.18632/aging.103883 · Cited by 15
“For example, experiments in an animal model of AD demonstrate that peripheral inflammatory stimuli can induce long-term innate immune memories in the brain that influence neuropathology later in life [108].”
BackgroundTrained immunity: novel perspectives in diabetes and associated complications
Liu, Y., Lei, Y., Dai, Z., Luo, C., Gong, Q., Li, Y., Xu, Y., & Huang, W. G. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1613602 · Cited by 14
“Peripheral injection of lipopolysaccharide (LPS) induces trained immunity in microglia, which subsequently exacerbates ischemic brain damage 1 month after LPS challenge (14).”
The role of maternal immune activation in immunological and neurological pathogenesis of autism
Liu, K., Huang, Y., Zhu, Y., Zhao, Y., & Kong, X. (2022) · Journal of Neurorestoratology · doi:10.1016/j.jnrt.2022.100030 · Cited by 13
An, X., Wang, J., Tong, L., Zhang, X., Fu, H., Zhang, J., Xie, H. Q., Huang, Y. H., & Jia, H. (2023) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2023.117233 · Cited by 14
Zhao, S., Zheng, J., Wang, L., Umpierre, A. D., Parusel, S., Xie, M., Dheer, A., Ayasoufi, K., Johnson, A. J., Richardson, J. R., et al. (2023) · Molecular Psychiatry · doi:10.1038/s41380-023-02128-6 · Cited by 13
“All experimental procedures were approved by the Mayo Clinic ’ s Institutional Animal Care and Use Committee (IACUC).”
MethodCortical microinfarcts potentiate recurrent ischemic injury through NLRP3-dependent trained immunity
Feng, Y., Lin, L., Wu, T., Feng, Y., Liang, F., Li, G., Li, Y., Guan, Y., Liu, S., Zhang, Y. L., et al. (2024) · Cell Death and Disease · doi:10.1038/s41419-023-06414-7 · Cited by 13
Metadata
- Authors
- Wendeln, A.-C., Degenhardt, K., Kaurani, L., Gertig, M., Ulas, T., Jain, G., Wagner, J., Häsler, L. M., Wild, K., Skodras, A., Blank, T., Staszewski, O., Datta, M., Centeno, T. P., Capece, V., Islam, M. R., Kerimoglu, C., Staufenbiel, M., Schultze, J. L., Beyer, M., Prinz, M., Jucker, M., Fischer, A., & Neher, J. J.
- Affiliations
- German Center for Neurodegenerative Diseases (DE)
- University of Bonn (DE)
- University of Freiburg (DE)
- Corresponding author
- Neher, Jonas J.
- ORCID
- Venue
- Nature
- Published
- 2018-04
- Volume
- 556
- Issue
- 7701
- Pages
- 332-338
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC6038912
- OpenAlex
- W2796983933
- Cited by
- 956
- References
- 51
- Citations by year
- 2026: 117 · 2025: 102 · 2024: 120 · 2023: 106 · 2022: 121 · 2021: 135 · 2020: 104 · 2019: 90 · 2018: 60
- FWCI
- 43.97
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DZNE Pub (submittedVersion)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Immunology and Microbiology › Immunology › Immune responses and vaccinations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Keywords
- trained immunity, immunological imprinting, immune tolerance, microglia, epigenetic reprogramming, neuroinflammation, Alzheimer's disease, beta-amyloidosis, stroke, neuropathology
- MeSH terms
- Alzheimer Disease, Amyloidosis, Animals, Brain, Disease Models, Animal, Female, Gene Expression Regulation, Humans, Immune Tolerance, Immunity, Innate, Immunologic Memory, Inflammation, Male, Nervous System Diseases, Microglia, Stroke, Epigenesis, Genetic, Mice
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