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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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“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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The Role of Cell Metabolism in Innate Immune Memory
Ferreira, A. V., Jorge, D.-A., & Netea, M. G. (2020) · Journal of Innate Immunity · doi:10.1159/000512280 · Cited by 89
Trained immunity: induction of an inflammatory memory in disease
Schlüter, T., van Elsas, Y., Priem, B., Ziogas, A., & Netea, M. G. (2025) · Cell Research · doi:10.1038/s41422-025-01171-y · Cited by 103
“16,18,22,151,157 Similar to Alzheimer ’ s disease associated neu-roin fl ammation, maladaptive central trained immunity associated with periodontitis, brain injury and western-like diet induced in fl ammation is induced by in fl ammasome signaling and IL-1 β .”
Therapeutic Epigenetic Reprogramming of Trained Immunity in Myeloid Cells
Rodríguez, R. M. A., Suárez-Álvarez, B., & López‐Larrea, C. (2018) · Trends in Immunology · doi:10.1016/j.it.2018.11.006 · Cited by 76
Sheng, L., Chen, M., Cai, K., Song, Y., Yu, D., Zhang, H., & Xu, G. (2019) · The FASEB Journal · doi:10.1096/fj.201900527r · Cited by 82
The Endotoxin Hypothesis of Parkinson's Disease
Brown, G. C., Camacho, M., & Williams‐Gray, C. H. (2023) · Movement Disorders · doi:10.1002/mds.29432 · Cited by 85
“This is related to the idea that neurodegeneration primes the brain for an excessive LPS response, so that an episode of endotoxemia may exacerbate an otherwiseindependent neurodegenerative process.(132,133) Alternatively, prior exposure to LPS may prime the brain to a subsequent neurodegenerative process.”
BackgroundMicroglia transcriptional states and their functional significance: Context drives diversity
Depp, C., Doman, J. L., Hingerl, M., Xia, J., & Stevens, B. (2025) · Immunity · doi:10.1016/j.immuni.2025.04.009 · Cited by 84
Cross-Talk of the CNS With Immune Cells and Functions in Health and Disease
Matejuk, A., Vandenbark, A. A., & Offner, H. (2021) · Frontiers in Neurology · doi:10.3389/fneur.2021.672455 · Cited by 81
“(135), for the first time, showed that immune memory occurs in the mouse brain via epigenetic changes and that it is predominantly mediated by microglia with an impact on neuropathology.”
BackgroundMicroglia and Wnt Pathways: Prospects for Inflammation in Alzheimer’s Disease
Yang, Y., & Zhang, Z. (2020) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2020.00110 · Cited by 76
“A high concentration of Aβ has a direct toxic influence on neurons, while a low concentration induces the exposure of signals on neurons and attracts microglia to phagocytose and degrade Aβ (Neniskyte et al., 2011; Wendeln et al., 2018).”
BackgroundSFRP1 modulates astrocyte-to-microglia crosstalk in acute and chronic neuroinflammation
Rueda‐Carrasco, J., Martín‐Bermejo, M. J., Pereyra, G., Mateo, M. I., Borroto, A., Brosseron, F., Kummer, M. P., Schwartz, S., López‐Atalaya, J. P., Alarcón, B., et al. (2021) · EMBO Reports · doi:10.15252/embr.202051696 · Cited by 79
“Furthermore, Hif1 a is involved in astrocytic proinflammatory activity (Wheeler et al , 2019) and its activity seems to be dysregulated in association with other genes genetically linked to AD risk, suggesting that HIF-1 a may be detrimental in AD pathology (Wendeln et al , 2018).”
Fruhwürth, S., Zetterberg, H., & Paludan, S. R. (2024) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2024.578342 · Cited by 77
“Repeated LPS injections before A β plaque deposition have been shown to decrease plaque load in APP23 mice and has been suggested to be due to epigenomic and transcriptomic alterations in microglia as part of innate immune memory (Wendeln et al., 2018).”
The Impact of Obesity on Microglial Function: Immune, Metabolic and Endocrine Perspectives
Alexaki, V. I. (2021) · Cells · doi:10.3390/cells10071584 · Cited by 84
“Chronically elevated IL-6 levels in the CNS due to IL-6 overexpression in astrocytes in transgenic mice promotes microglial density, inflammation exemplified by increased IL-1β, TNF, IL-10, IL-6 and MHCII expression, and neurologic disease [322,323].”
BackgroundInfluentialCastro-Sánchez, S., García-Yagüe, Á. J., Kügler, S., & Lastres-Becker, I. (2019) · Redox Biology · doi:10.1016/j.redox.2019.101118 · Cited by 76
Trained Immunity and Local Innate Immune Memory in the Lung
Netea, M. G., & Joosten, L. A. B. (2018) · Cell · doi:10.1016/j.cell.2018.11.007 · Cited by 79
Interaction of microglia with infiltrating immune cells in the different phases of stroke
Berchtold, D., Priller, J., Meisel, C., & Meisel, A. (2020) · Brain Pathology · doi:10.1111/bpa.12911 · Cited by 77
“Microglia activation and neuronal damage was also increased in this model 7 days after stroke (115).”
BackgroundTrained Immunity Characteristics Are Associated With Progressive Cerebral Small Vessel Disease
Noz, M. P., ter Telgte, A., Wiegertjes, K., Joosten, L. A. B., Netea, M. G., de Leeuw, F., & Riksen, N. P. (2018) · Stroke · doi:10.1161/strokeaha.118.023192 · Cited by 75
Castranio, E. L., Hasel, P., Haure‐Mirande, J., Ramirez Jimenez, A. V., Hamilton, B. W., Kim, R. D., Glabe, C. G., Wang, M., Zhang, B., Gandy, S., et al. (2023) · Alzheimer's & Dementia · doi:10.1002/alz.12821 · Cited by 74
Macrophage Responses to Environmental Stimuli During Homeostasis and Disease
Rasheed, A., & Rayner, K. J. (2021) · Endocrine Reviews · doi:10.1210/endrev/bnab004 · Cited by 83
"Lipopolysaccharide-induced animal models for neuroinflammation – An overview."
Silva, A., Fiadeiro, M. B., Bernardino, L. I., Fonseca, C. P., Baltazar, G., & Cristóvão, A. C. (2023) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2023.578273 · Cited by 77
“The dose for LPS exposure goes from 0.25 mg/kg to 200 mg/kg of LPS (Zakaria et al., 2017; Wendeln et al., 2018; He et al., 2019), being the response to each dose and paradigm variable, as shown in Table 1 and respective references.”
MethodInfluentialGampierakis, I. A., Koutmani, Y., Semitekolou, M., Morianos, I., Polissidis, A., Katsouda, A., Charalampopoulos, I., Xanthou, G., Gravanis, A., & Karalis, K. P. (2020) · Molecular Psychiatry · doi:10.1038/s41380-020-0651-6 · Cited by 75
The role of microglia in early neurodevelopment and the effects of maternal immune activation
Mastenbroek, L., Kooistra, S. M., Eggen, B. J. L., & Prins, J. R. (2024) · Seminars in Immunopathology · doi:10.1007/s00281-024-01017-6 · Cited by 82
Interleukin-10 improves stroke outcome by controlling the detrimental Interleukin-17A response
Piepke, M., Clausen, B. H., Ludewig, P., Vienhues, J. H., Bedke, T., Javidi, E., Rissiek, B., Jank, L., Brockmann, L., Sandrock, I., et al. (2021) · Journal of Neuroinflammation · doi:10.1186/s12974-021-02316-7 · Cited by 75
“Among potential anti-inflammatory pathways, IL-10 holds a prominent role, due to its strong immunomodulatory and neuroprotective effects [6, 7].”
BackgroundSelf-citationTargeting NLRP3-Mediated Neuroinflammation in Alzheimer’s Disease Treatment
Barczuk, J., Siwecka, N., Lusa, W., Rozpędek‐Kamińska, W., Kucharska, E., & Majsterek, I. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23168979 · Cited by 76
Rui, W., Xiao, H., Fan, Y., Ma, Z., Xiao, M., Li, S., & Shi, J. (2021) · Journal of Neuroinflammation · doi:10.1186/s12974-021-02329-2 · Cited by 79
“To confirm the role of pyroptosis on neuroinflammation in an in vivo AD model, we intraperitoneally injected a low dose of LPS into 5 × FAD and WT mice to induce peripheral inflammation with LPS not crossing the blood–brain barrier as previously reported [27].”
MethodQiang, W., Cai, W., Yang, Q., Yang, L., Dai, Y., Zhao, Z., Yin, J., Li, Y., Li, Q., Wang, Y., et al. (2018) · Neuroscience · doi:10.1016/j.neuroscience.2018.10.041 · Cited by 70
Frederiksen, H. R., Haukedal, H., & Freude, K. (2019) · BioMed Research International · doi:10.1155/2019/7420189 · Cited by 63
“In this study, two types of immunological imprinting were distinguished from one another, namely, training and tolerance, which can respectively enhance or suppress the inflammation [133].”
BackgroundNagy, E. E., Frigy, A., Sz�sz, J., & Horv�th, E. (2020) · Experimental and Therapeutic Medicine · doi:10.3892/etm.2020.8933 · Cited by 73
“It has been demonstrated in an endothelin‑induced focal cerebral ischemia model, that peripheral administration of TNFα can induce IL‑4 and IL‑10 and suppress IFNγ in the brain if applied on the innate immune system training background (repeated administration of LPS) (102).”
BackgroundInfluentialMacrophage reprogramming for therapy
Bart, V. M. T., Pickering, R. J., Taylor, P. R., & Ipseiz, N. (2020) · Immunology · doi:10.1111/imm.13300 · Cited by 73
Chavakis, T., Wielockx, B., & Hajishengallis, G. (2021) · Annual Review of Physiology · doi:10.1146/annurev-physiol-052521-013627 · Cited by 75
TLR4 is a regulator of trained immunity in a murine model of Duchenne muscular dystrophy
Bhattarai, S., Li, Q., Ding, J., Liang, F., Gusev, E., Lapohos, O., Fonseca, G. J., Kaufmann, E., Divangahi, M., & Petrof, B. J. (2022) · Nature Communications · doi:10.1038/s41467-022-28531-1 · Cited by 72
Repeated LPS induces training and tolerance of microglial responses across brain regions
Kim, J. S., Sullivan, O., Lee, K., Jao, J., Tamayo, J., Madany, A. M., Wong, B., Ashwood, P., & Ciernia, A. V. (2024) · Journal of Neuroinflammation · doi:10.1186/s12974-024-03198-1 · Cited by 74
“Repeated LPS induces long-lasting immune training and tolerance in brain microglia that has been shown to persist for at least 6 months [19].”
BackgroundMethodResultInfluentialDesplats, P., Gutierrez, A. M., Antonelli, M. C., & Frasch, M. G. (2019) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2019.10.013 · Cited by 74
Quinn, S. M., Cunningham, K. T., Raverdeau, M., Walsh, R. J., Curham, L. M., Malara, A., & Mills, K. H. G. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.01109 · Cited by 70
“Immunological memory was traditionally thought to be confined to the adaptive immune system, however, recent studies have shown that the innate immune system has a type of memory or can be trained (36, 37).”
BackgroundPritchard, A. B., Fabian, Z., Lawrence, C. L., Morton, G., Crean, S., & Alder, J. E. (2022) · Journal of Alzheimer s Disease · doi:10.3233/jad-215054 · Cited by 72
“Both immunological activation and tolerance [80, 81] could explain how chronic exposure to even medium and low levels of P. gingivalis LPS could lead to neurodegeneration by induction of pro-inflammatory pathways and activation of microglia and it is plausible that a low concentration of P.…”
Yoon, S.-H., Kim, C., Lee, E., Lee, C., Lee, K.-S., Lee, J., Park, H., Choi, B., Hwang, I., Kim, J., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-56097-1 · Cited by 78
“1a) 25 .”
Yang, Y., He, Z., Xing, Z., Zuo, Z., Yuan, L., Wu, Y., Jiang, M. H., Qi, F., & Yao, Z. (2020) · Journal of Neuroinflammation · doi:10.1186/s12974-020-01741-4 · Cited by 67
He, X., Xu, J., Li, G., Li, M., Li, L., Pei, Z., Zhang, L., & Hu, X. (2020) · Cell Death and Disease · doi:10.1038/s41419-020-03072-x · Cited by 64
Mechanisms of immune effector cell‐associated neurotoxicity syndrome after CAR‐T treatment
Gu, T., Hu, K., Si, X., Hu, Y., & Huang, H. (2022) · WIREs Mechanisms of Disease · doi:10.1002/wsbm.1576 · Cited by 69
“Further infiltration of cytokines and immunocytes into the CNS triggers noninfectious neuroinflammation and corresponding symptoms (Galic et al., 2012; Turtle et al., 2016; Wendeln et al., 2018).”
BackgroundHuang, M., Malovic, E., Ealy, A., Jin, H., Anantharam, V., Kanthasamy, A., & Kanthasamy, A. G. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1052925 · Cited by 64
“Recently, an intriguing concept has emerged that such insult-induced microglia can also shape immune-response memories through epigenetic reprogramming, termed trained immunity (2, 3).”
BackgroundInfluentialExploring glia to better understand Alzheimer’s disease
Kim, Y. S., Jung, H. M., & Yoon, B. (2018) · Animal Cells and Systems · doi:10.1080/19768354.2018.1508498 · Cited by 68
“However, in APP23-Transgenic mice which express human APP with Thy-1 promoter, repetitive inflammatory stimulation was shown to decrease the formation of Aβ plaques (Wendeln et al. 2018).”
BackgroundTRIM9-Mediated Resolution of Neuroinflammation Confers Neuroprotection upon Ischemic Stroke in Mice
Zeng, J., Wang, Y., Luo, Z., Chang, L.-C., Yoo, J., Yan, H., Choi, Y., Xie, X., Deverman, B. E., Gradinaru, V., et al. (2019) · Cell Reports · doi:10.1016/j.celrep.2018.12.055 · Cited by 65
“Because there is a significant sex effect on the pathology of brain ischemia (Liu et al., 2009; Wendeln et al., 2018), where both male and female mice were compared, only female aged C57BL/6J mice with 70-week-old were used in the present study.”
Midbrain microglia mediate a specific immunosuppressive response under inflammatory conditions
Abellanas, M. A., Zamarbide, M., Basurco, L., Luquin, E., García‐Granero, M., Clavero, P., Martín‐Úriz, P. S., Vilas‐Zornoza, A., Mengual, E., Hervás‐Stubbs, S., et al. (2019) · Journal of Neuroinflammation · doi:10.1186/s12974-019-1628-8 · Cited by 69
Innate immunological memory: from plants to animals
Sharrock, J., & Sun, J. C.-Y. (2020) · Current Opinion in Immunology · doi:10.1016/j.coi.2019.12.001 · Cited by 65
Hajishengallis, G., Li, X., Divaris, K., & Chavakis, T. (2022) · Periodontology 2000 · doi:10.1111/prd.12421 · Cited by 70
Nahrendorf, W., Ivens, A. C., & Spence, P. J. (2021) · eLife · doi:10.7554/elife.63838 · Cited by 57
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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