{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T10:03:05Z","timestamp":1790762585313,"version":"4.1.0"},"reference-count":104,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T00:00:00Z","timestamp":1790553600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Research Foundation (NRF), Republic of Korea","award":["2021R1A2C2010920"],"award-info":[{"award-number":["2021R1A2C2010920"]}]},{"award":["2021R1A2C2010920"],"award-info":[{"award-number":["2021R1A2C2010920"]}],"id":[{"id":"https:\/\/ror.org\/013aysd81","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Alzheimer\u2019s disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of amyloid-beta (A\u03b2) plaques and neurofibrillary tangles. Beyond these hallmark pathological features, the complex pathogenesis of AD involves cellular dysfunctions associated with chronic oxidative stress and neuroinflammation. Central to these inflammatory pathways is the extracellular release of the nuclear protein high-mobility group box 1 (HMGB1) from neurons and microglia. Extracellular HMGB1 disrupts homeostatic and reparative microglial functions, impairing the phagocytic clearance of amyloid-beta and driving neuroinflammation to accelerate AD pathogenesis. Consequently, targeting HMGB1 offers a promising therapeutic strategy for AD. This review examines recent progress and key insights regarding HMGB1-associated neuroinflammatory pathology in AD. We evaluate its regulation across transcriptional upregulation, cellular redistribution, age-related alterations, and A\u03b2-associated pathology. We further detail the pleiotropic effects of extracellular HMGB1, including neuroinflammation, defective A\u03b2 phagocytic clearance, and genomic instability. Finally, we discuss the potential clinical utility of targeting HMGB1 to mitigate AD progression and provide HMGB1-related perspectives for future studies.<\/jats:p>","DOI":"10.3390\/ijms27198681","type":"journal-article","created":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T16:50:54Z","timestamp":1790614254000},"page":"8681","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["HMGB1 in Amyloid-Beta Pathology: Mechanistic Insights and Therapeutic Implications for Alzheimer\u2019s Disease"],"prefix":"10.3390","volume":"27","author":[{"given":"Song-I","family":"Seol","sequence":"first","affiliation":[{"name":"Department of Anatomy, Inha University School of Medicine, Incheon 22212, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-8283-8525","authenticated-orcid":false,"given":"Ji-Eun","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Physical Education and Sport Science Institute, Korea National Sport University, Seoul 05541, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-6983-1611","authenticated-orcid":false,"given":"Dashdulam","family":"Davaanyam","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Inha University School of Medicine, Incheon 22212, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"So-Young","family":"Park","sequence":"additional","affiliation":[{"name":"Neuromed R&D Institute, Neuromed Inc., Rm 605 Industry-Academic Cooperation Building-B, 1071, An yang cheon-ro, Yangcheon-gu, Seoul 07953, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eun-Hwa","family":"Lee","sequence":"additional","affiliation":[{"name":"Ewha Medical Research Institute, College of Medicine, Ewha Womans University, Seoul 07985, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pyung-Lim","family":"Han","sequence":"additional","affiliation":[{"name":"Neuromed R&D Institute, Neuromed Inc., Rm 605 Industry-Academic Cooperation Building-B, 1071, An yang cheon-ro, Yangcheon-gu, Seoul 07953, Republic of Korea"},{"name":"Department of Brain and Cognitive Sciences, Scranton College, Ewha Womans University, Seoul 03760, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7048-8983","authenticated-orcid":false,"given":"Tae-Kyung","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Physical Education and Sport Science Institute, Korea National Sport University, Seoul 05541, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ja-Kyeong","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Inha University School of Medicine, Incheon 22212, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1038\/s41572-021-00269-y","article-title":"Alzheimer disease","volume":"7","author":"Knopman","year":"2021","journal-title":"Nat. Rev. Dis. Primers."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1038\/s41577-024-01104-7","article-title":"Neuroinflammation in Alzheimer disease","volume":"25","author":"Heneka","year":"2025","journal-title":"Nat. Rev. Immunol."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Behl, C. (2024). In 2024, the amyloid-cascade-hypothesis still remains a working hypothesis, no less but certainly no more. Front. Aging Neurosci., 16.","DOI":"10.3389\/fnagi.2024.1459224"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"31895","DOI":"10.1038\/srep31895","article-title":"HMGB1, a pathogenic molecule that induces neurite degeneration via TLR4-MARCKS, is a potential therapeutic target for Alzheimer\u2019s disease","volume":"6","author":"Fujita","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Seol, S.I., Davaanyam, D., Oh, S.A., Lee, E.H., Han, P.L., Kim, S.W., and Lee, J.K. (2024). Age-Dependent and A\u03b2-Induced Dynamic Changes in the Subcellular Localization of HMGB1 in Neurons and Microglia in the Brains of an Animal Model of Alzheimer\u2019s Disease. Cells, 13.","DOI":"10.3390\/cells13020189"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Paudel, Y.N., Angelopoulou, E., Piperi, C., Othman, I., Aamir, K., and Shaikh, M.F. (2020). Impact of HMGB1, RAGE, and TLR4 in Alzheimer\u2019s Disease (AD): From Risk Factors to Therapeutic Targeting. Cells, 9.","DOI":"10.3390\/cells9020383"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"106115","DOI":"10.1016\/j.neuint.2026.106115","article-title":"Redox-sensitive high mobility group box 1 (HMGB1) protein is a multipotent regulator in the pathogenesis of Alzheimer\u2019s disease","volume":"193","author":"Salminen","year":"2026","journal-title":"Neurochem. Int."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1016\/S0006-291X(03)00024-X","article-title":"Role of high mobility group protein-1 (HMG1) in amyloid-beta homeostasis","volume":"301","author":"Takata","year":"2003","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1189\/jlb.1212662","article-title":"The many faces of HMGB1: Molecular structure-functional activity in inflammation, apoptosis, and chemotaxis","volume":"93","author":"Yang","year":"2013","journal-title":"J. Leukoc. Biol."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Kwak, M.S., Kim, H.S., Lee, B., Kim, Y.H., Son, M., and Shin, J.S. (2020). Immunological Significance of HMGB1 Post-Translational Modification and Redox Biology. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.01189"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"824","DOI":"10.1038\/s41577-023-00894-6","article-title":"The multifunctional protein HMGB1: 50 years of discovery","volume":"23","author":"Tang","year":"2023","journal-title":"Nat. Rev. Immunol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"117204","DOI":"10.1016\/j.intimp.2026.117204","article-title":"HMGB1 signalling in Alzheimer\u2019s disease: Pathogenic roles and therapeutic prospects","volume":"187","author":"Tyagi","year":"2026","journal-title":"Int. Immunopharmacol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1038\/nature08512","article-title":"HMGB proteins function as universal sentinels for nucleic-acid-mediated innate immune responses","volume":"462","author":"Yanai","year":"2009","journal-title":"Nature"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1083\/jcb.200911078","article-title":"Endogenous HMGB1 regulates autophagy","volume":"190","author":"Tang","year":"2010","journal-title":"J. Cell Biol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1016\/j.intimp.2018.12.027","article-title":"HMGB1 gene silencing inhibits neuroinflammation via down-regulation of NF-\u03baB signaling in primary hippocampal neurons induced by A\u03b2(25-35)","volume":"67","author":"Nan","year":"2019","journal-title":"Int. Immunopharmacol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"995","DOI":"10.1093\/embo-reports\/kvf198","article-title":"The nuclear protein HMGB1 is secreted by monocytes via a non-classical, vesicle-mediated secretory pathway","volume":"3","author":"Gardella","year":"2002","journal-title":"EMBO Rep."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"5551","DOI":"10.1093\/emboj\/cdg516","article-title":"Monocytic cells hyperacetylate chromatin protein HMGB1 to redirect it towards secretion","volume":"22","author":"Bonaldi","year":"2003","journal-title":"EMBO J."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2345","DOI":"10.1080\/15548627.2020.1826690","article-title":"Secretory autophagy machinery and vesicular trafficking are involved in HMGB1 secretion","volume":"17","author":"Kim","year":"2021","journal-title":"Autophagy"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"5800","DOI":"10.4049\/jimmunol.0801873","article-title":"HMGB1 is phosphorylated by classical protein kinase C and is secreted by a calcium-dependent mechanism","volume":"182","author":"Oh","year":"2009","journal-title":"J. Immunol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"359","DOI":"10.2119\/molmed.2011.00203","article-title":"Poly(ADP-ribosyl)ation of high mobility group box 1 (HMGB1) protein enhances inhibition of efferocytosis","volume":"18","author":"Davis","year":"2012","journal-title":"Mol. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1038\/ki.2014.217","article-title":"High-mobility group box 1 is a novel deacetylation target of Sirtuin1","volume":"87","author":"Rabadi","year":"2015","journal-title":"Kidney Int."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e31364","DOI":"10.1002\/jcp.31364","article-title":"SIRT2 regulates high mobility group protein B1 nucleoplasmic shuttle and degradation via deacetylation in microglia","volume":"239","author":"Xing","year":"2024","journal-title":"J. Cell. Physiol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e13967","DOI":"10.1111\/acel.13967","article-title":"Cooperative effects of SIRT1 and SIRT2 on APP acetylation","volume":"22","author":"Li","year":"2023","journal-title":"Aging Cell"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2143","DOI":"10.1248\/bpb.b24-00203","article-title":"HMGB1 Promotes Accelerated Fracture Healing in Traumatic Brain Injury through PINK1\/Parkin-Mediated Mitochondrial Autophagy","volume":"47","author":"Chen","year":"2024","journal-title":"Biol. Pharm. Bull."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Kim, S.W., Oh, S.A., Seol, S.I., Davaanyam, D., and Lee, J.K. (2022). Cytosolic HMGB1 Mediates LPS-Induced Autophagy in Microglia by Interacting with NOD2 and Suppresses Its Proinflammatory Function. Cells, 11.","DOI":"10.3390\/cells11152410"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1186\/s12974-019-1673-3","article-title":"HMGB1\/RAGE axis mediates stress-induced RVLM neuroinflammation in mice via impairing mitophagy flux in microglia","volume":"17","author":"Zhang","year":"2020","journal-title":"J. Neuroinflammation"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1519","DOI":"10.1084\/jem.20120189","article-title":"Mutually exclusive redox forms of HMGB1 promote cell recruitment or proinflammatory cytokine release","volume":"209","author":"Venereau","year":"2012","journal-title":"J. Exp. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1084\/jem.20111739","article-title":"HMGB1 promotes recruitment of inflammatory cells to damaged tissues by forming a complex with CXCL12 and signaling via CXCR4","volume":"209","author":"Schiraldi","year":"2012","journal-title":"J. Exp. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"101203","DOI":"10.1016\/j.redox.2019.101203","article-title":"Peroxiredoxin-mediated disulfide bond formation is required for nucleocytoplasmic translocation and secretion of HMGB1 in response to inflammatory stimuli","volume":"24","author":"Kwak","year":"2019","journal-title":"Redox Biol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1124\/jpet.116.237503","article-title":"Oxidative Stress and the Central Nervous System","volume":"360","author":"Salim","year":"2017","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1038\/s42003-020-1010-5","article-title":"Aging increases vulnerability to stress-induced depression via upregulation of NADPH oxidase in mice","volume":"3","author":"Lee","year":"2020","journal-title":"Commun. Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1038\/s12276-026-01641-2","article-title":"Repeated treatment with short-term mild stress reverses aging- and stress-induced emotional and social behavioral deficits","volume":"58","author":"Lee","year":"2026","journal-title":"Exp. Mol. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1111\/j.1471-4159.2008.05769.x","article-title":"Behavioral stress accelerates plaque pathogenesis in the brain of Tg2576 mice via generation of metabolic oxidative stress","volume":"108","author":"Lee","year":"2009","journal-title":"J. Neurochem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1016\/j.redox.2017.10.014","article-title":"Oxidative stress and the amyloid beta peptide in Alzheimer\u2019s disease","volume":"14","author":"Cheignon","year":"2018","journal-title":"Redox Biol."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Buccellato, F.R., D\u2019Anca, M., Fenoglio, C., Scarpini, E., and Galimberti, D. (2021). Role of Oxidative Damage in Alzheimer\u2019s Disease and Neurodegeneration: From Pathogenic Mechanisms to Biomarker Discovery. Antioxidants, 10.","DOI":"10.3390\/antiox10091353"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1722","DOI":"10.1126\/science.1168988","article-title":"CD24 and Siglec-10 selectively repress tissue damage-induced immune responses","volume":"323","author":"Chen","year":"2009","journal-title":"Science"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"832","DOI":"10.1038\/ni.2376","article-title":"Tumor-infiltrating DCs suppress nucleic acid-mediated innate immune responses through interactions between the receptor TIM-3 and the alarmin HMGB1","volume":"13","author":"Chiba","year":"2012","journal-title":"Nat. Immunol."},{"key":"ref_38","first-page":"4805","article-title":"Receptor for advanced glycation end products-binding COOH-terminal motif of amphoterin inhibits invasive migration and metastasis","volume":"62","author":"Huttunen","year":"2002","journal-title":"Cancer Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1129","DOI":"10.1038\/sj.emboj.7601552","article-title":"A novel pathway of HMGB1-mediated inflammatory cell recruitment that requires Mac-1-integrin","volume":"26","author":"Orlova","year":"2007","journal-title":"EMBO J."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"5067","DOI":"10.4049\/jimmunol.180.7.5067","article-title":"High mobility group box 1 protein binding to lipopolysaccharide facilitates transfer of lipopolysaccharide to CD14 and enhances lipopolysaccharide-mediated TNF-alpha production in human monocytes","volume":"180","author":"Youn","year":"2008","journal-title":"J. Immunol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1084\/jem.20160217","article-title":"High mobility group box 1 orchestrates tissue regeneration via CXCR4","volume":"215","author":"Tirone","year":"2018","journal-title":"J. Exp. Med."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1083\/jcb.200304135","article-title":"Extracellular HMGB1, a signal of tissue damage, induces mesoangioblast migration and proliferation","volume":"164","author":"Palumbo","year":"2004","journal-title":"J. Cell Biol."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Tancharoen, S., Gando, S., Binita, S., Nagasato, T., Kikuchi, K., Nawa, Y., Dararat, P., Yamamoto, M., Narkpinit, S., and Maruyama, I. (2016). HMGB1 Promotes Intraoral Palatal Wound Healing through RAGE-Dependent Mechanisms. Int. J. Mol. Sci., 17.","DOI":"10.3390\/ijms17111961"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1083\/jcb.201206006","article-title":"p53-dependent release of Alarmin HMGB1 is a central mediator of senescent phenotypes","volume":"201","author":"Davalos","year":"2013","journal-title":"J. Cell Biol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"7946","DOI":"10.1523\/JNEUROSCI.1161-16.2016","article-title":"The Alarmin HMGB1 Mediates Age-Induced Neuroinflammatory Priming","volume":"36","author":"Fonken","year":"2016","journal-title":"J. Neurosci."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"e70051","DOI":"10.1111\/jnc.70051","article-title":"The Role of Glial Cell Senescence in Alzheimer\u2019s Disease","volume":"169","author":"Alshaebi","year":"2025","journal-title":"J. Neurochem."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/j.bbi.2018.07.012","article-title":"Stress and aging act through common mechanisms to elicit neuroinflammatory priming","volume":"73","author":"Fonken","year":"2018","journal-title":"Brain Behav. Immun."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1523\/JNEUROSCI.3561-14.2015","article-title":"Stress induces the danger-associated molecular pattern HMGB-1 in the hippocampus of male Sprague Dawley rats: A priming stimulus of microglia and the NLRP3 inflammasome","volume":"35","author":"Weber","year":"2015","journal-title":"J. Neurosci."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1016\/j.bbi.2015.10.009","article-title":"The redox state of the alarmin HMGB1 is a pivotal factor in neuroinflammatory and microglial priming: A role for the NLRP3 inflammasome","volume":"55","author":"Frank","year":"2016","journal-title":"Brain Behav. Immun."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1145","DOI":"10.1007\/s11011-022-00932-7","article-title":"Potential of nobiletin against Alzheimer\u2019s disease through inhibiting neuroinflammation","volume":"37","author":"Chai","year":"2022","journal-title":"Metab. Brain Dis."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1186\/s12974-016-0670-z","article-title":"HMGB1 and thrombin mediate the blood-brain barrier dysfunction acting as biomarkers of neuroinflammation and progression to neurodegeneration in Alzheimer\u2019s disease","volume":"13","author":"Festoff","year":"2016","journal-title":"J. Neuroinflammation"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.jprot.2016.03.022","article-title":"Identification of proteins that are differentially expressed in brains with Alzheimer\u2019s disease using iTRAQ labeling and tandem mass spectrometry","volume":"139","author":"Minjarez","year":"2016","journal-title":"J. Proteom."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"109419","DOI":"10.1016\/j.celrep.2021.109419","article-title":"Tau oligomer induced HMGB1 release contributes to cellular senescence and neuropathology linked to Alzheimer\u2019s disease and frontotemporal dementia","volume":"36","author":"Gaikwad","year":"2021","journal-title":"Cell Rep."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1038\/s41467-020-14353-6","article-title":"YAP-dependent necrosis occurs in early stages of Alzheimer\u2019s disease and regulates mouse model pathology","volume":"11","author":"Tanaka","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1186\/s13195-025-01682-1","article-title":"Delta-opioid receptor signaling alleviates neuropathology and cognitive impairment in the mouse model of Alzheimer\u2019s disease by regulating microglia homeostasis and inhibiting HMGB1 pathway","volume":"17","author":"Xu","year":"2025","journal-title":"Alzheimers Res. Ther."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"2482","DOI":"10.1038\/s41401-022-00888-5","article-title":"Trilobatin rescues cognitive impairment of Alzheimer\u2019s disease by targeting HMGB1 through mediating SIRT3\/SOD2 signaling pathway","volume":"43","author":"Gao","year":"2022","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Fu, J., Wang, R., He, J., Liu, X., Wang, X., Yao, J., Liu, Y., Ran, C., Ye, Q., and He, Y. (2025). Pathogenesis and therapeutic applications of microglia receptors in Alzheimer\u2019s disease. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1508023"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1002\/glia.1072","article-title":"Inflammatory repertoire of Alzheimer\u2019s disease and nondemented elderly microglia in vitro","volume":"35","author":"Lue","year":"2001","journal-title":"Glia"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"712","DOI":"10.1126\/science.aad8373","article-title":"Complement and microglia mediate early synapse loss in Alzheimer mouse models","volume":"352","author":"Hong","year":"2016","journal-title":"Science"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"837","DOI":"10.1038\/s43587-022-00281-1","article-title":"Complement C1q-dependent excitatory and inhibitory synapse elimination by astrocytes and microglia in Alzheimer\u2019s disease mouse models","volume":"2","author":"Dejanovic","year":"2022","journal-title":"Nat. Aging"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1016\/j.bbi.2025.02.007","article-title":"PDE4 inhibition alleviates HMGB1\/C1q\/C3-mediated excessive phagocytic pruning of synapses by microglia and depressive-like behaviors in mice","volume":"126","author":"Zhao","year":"2025","journal-title":"Brain Behav. Immun."},{"key":"ref_62","first-page":"685739","article-title":"Microglial Amyloid-\u03b21-40 Phagocytosis Dysfunction Is Caused by High-Mobility Group Box Protein-1: Implications for the Pathological Progression of Alzheimer\u2019s Disease","volume":"2012","author":"Takata","year":"2012","journal-title":"Int. J. Alzheimers Dis."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"6448","DOI":"10.1073\/pnas.95.11.6448","article-title":"Diffusible, nonfibrillar ligands derived from Abeta1-42 are potent central nervous system neurotoxins","volume":"95","author":"Lambert","year":"1998","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1038\/416535a","article-title":"Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo","volume":"416","author":"Walsh","year":"2002","journal-title":"Nature"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"32","DOI":"10.2174\/1567205012666141218140953","article-title":"Amyloid-beta protein clearance and degradation (ABCD) pathways and their role in Alzheimer\u2019s disease","volume":"12","author":"Baranello","year":"2015","journal-title":"Curr. Alzheimer Res."},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Ries, M., and Sastre, M. (2016). Mechanisms of A\u03b2 Clearance and Degradation by Glial Cells. Front. Aging Neurosci., 8.","DOI":"10.3389\/fnagi.2016.00160"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1038\/nrneurol.2015.119","article-title":"Clearance systems in the brain-implications for Alzheimer disease","volume":"11","author":"Carare","year":"2015","journal-title":"Nat. Rev. Neurol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1774","DOI":"10.1126\/science.1197623","article-title":"Decreased clearance of CNS beta-amyloid in Alzheimer\u2019s disease","volume":"330","author":"Mawuenyega","year":"2010","journal-title":"Science"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"C1267","DOI":"10.1152\/ajpcell.00152.2010","article-title":"HMGB1 inhibits macrophage activity in efferocytosis through binding to the alphavbeta3-integrin","volume":"299","author":"Friggeri","year":"2010","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"4240","DOI":"10.4049\/jimmunol.181.6.4240","article-title":"High mobility group protein-1 inhibits phagocytosis of apoptotic neutrophils through binding to phosphatidylserine","volume":"181","author":"Liu","year":"2008","journal-title":"J. Immunol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"880","DOI":"10.1002\/jnr.20340","article-title":"High mobility group box protein-1 inhibits microglial Abeta clearance and enhances Abeta neurotoxicity","volume":"78","author":"Takata","year":"2004","journal-title":"J. Neurosci. Res."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"3006","DOI":"10.1093\/brain\/awl249","article-title":"Role of toll-like receptor signaling in Abeta uptake and clearance","volume":"129","author":"Tahara","year":"2006","journal-title":"Brain"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1007\/s10571-014-0101-6","article-title":"Microglial A\u03b2 receptors in Alzheimer\u2019s disease","volume":"35","author":"Yu","year":"2015","journal-title":"Cell. Mol. Neurobiol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"2030","DOI":"10.1038\/ncomms3030","article-title":"Scara1 deficiency impairs clearance of soluble amyloid-\u03b2 by mononuclear phagocytes and accelerates Alzheimer\u2019s-like disease progression","volume":"4","author":"Frenkel","year":"2013","journal-title":"Nat. Commun."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"115052","DOI":"10.1016\/j.celrep.2024.115052","article-title":"Microglia degrade Alzheimer\u2019s amyloid-beta deposits extracellularly via digestive exophagy","volume":"43","author":"Jacquet","year":"2024","journal-title":"Cell Rep."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"243ra86","DOI":"10.1126\/scitranslmed.3009093","article-title":"TREM2 mutations implicated in neurodegeneration impair cell surface transport and phagocytosis","volume":"6","author":"Kleinberger","year":"2014","journal-title":"Sci. Transl. Med."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1023","DOI":"10.1016\/j.neuron.2018.01.031","article-title":"TREM2 Is a Receptor for \u03b2-Amyloid that Mediates Microglial Function","volume":"97","author":"Zhao","year":"2018","journal-title":"Neuron"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1186\/s13024-018-0298-9","article-title":"New insights into the role of TREM2 in Alzheimer\u2019s disease","volume":"13","author":"Gratuze","year":"2018","journal-title":"Mol. Neurodegener."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1038\/s41593-018-0296-9","article-title":"Loss of TREM2 function increases amyloid seeding but reduces plaque-associated ApoE","volume":"22","author":"Parhizkar","year":"2019","journal-title":"Nat. Neurosci."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"8354","DOI":"10.1523\/JNEUROSCI.0616-08.2008","article-title":"Microglial dysfunction and defective beta-amyloid clearance pathways in aging Alzheimer\u2019s disease mice","volume":"28","author":"Hickman","year":"2008","journal-title":"J. Neurosci."},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Grimm, M.O., Mett, J., Stahlmann, C.P., Haupenthal, V.J., Zimmer, V.C., and Hartmann, T. (2013). Neprilysin and A\u03b2 Clearance: Impact of the APP Intracellular Domain in NEP Regulation and Implications in Alzheimer\u2019s Disease. Front. Aging Neurosci., 5.","DOI":"10.3389\/fnagi.2013.00098"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"106426","DOI":"10.1016\/j.nbd.2024.106426","article-title":"The relationship between inflammation, impaired glymphatic system, and neurodegenerative disorders: A vicious cycle","volume":"192","author":"Cai","year":"2024","journal-title":"Neurobiol. Dis."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1186\/s42466-021-00102-7","article-title":"Glymphatic system, AQP4, and their implications in Alzheimer\u2019s disease","volume":"3","author":"Silva","year":"2021","journal-title":"Neurol. Res. Pract."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1093\/hmg\/ddu475","article-title":"Comprehensive phosphoproteome analysis unravels the core signaling network that initiates the earliest synapse pathology in preclinical Alzheimer\u2019s disease brain","volume":"24","author":"Tagawa","year":"2015","journal-title":"Hum. Mol. Genet."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"104901","DOI":"10.1016\/j.neuint.2020.104901","article-title":"Synaptic elimination by microglia and disturbed higher brain functions","volume":"142","author":"Miyanishi","year":"2021","journal-title":"Neurochem. Int."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1186\/s12974-023-02756-3","article-title":"HMGB1 mediates synaptic loss and cognitive impairment in an animal model of sepsis-associated encephalopathy","volume":"20","author":"Yin","year":"2023","journal-title":"J. Neuroinflammation"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"115583","DOI":"10.1016\/j.expneurol.2025.115583","article-title":"HMGB1 Box A gene therapy reverses cognitive and neuropathological features in AlCl3\/D-galactose rat model of Alzheimer\u2019s disease","volume":"397","author":"Supasai","year":"2026","journal-title":"Exp. Neurol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1043","DOI":"10.1096\/fj.09-139634","article-title":"RAGE-dependent signaling in microglia contributes to neuroinflammation, Abeta accumulation, and impaired learning\/memory in a mouse model of Alzheimer\u2019s disease","volume":"24","author":"Fang","year":"2010","journal-title":"FASEB J."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1016\/j.bbi.2016.10.012","article-title":"Toll-like receptor 4-dependent glial cell activation mediates the impairment in memory establishment induced by \u03b2-amyloid oligomers in an acute mouse model of Alzheimer\u2019s disease","volume":"60","author":"Balducci","year":"2017","journal-title":"Brain Behav. Immun."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1186\/s12974-021-02274-0","article-title":"HMGB1 mediates cognitive impairment caused by the NLRP3 inflammasome in the late stage of traumatic brain injury","volume":"18","author":"Tan","year":"2021","journal-title":"J. Neuroinflammation"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1111\/psyg.12794","article-title":"HMGB1 augments cognitive impairment in sepsis-associated encephalopathy by binding to MD-2 and promoting NLRP3-induced neuroinflammation","volume":"22","author":"Xiong","year":"2022","journal-title":"Psychogeriatrics"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1002\/mc.20544","article-title":"HMGB1: The jack-of-all-trades protein is a master DNA repair mechanic","volume":"48","author":"Lange","year":"2009","journal-title":"Mol. Carcinog."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1038\/nn.3356","article-title":"Physiologic brain activity causes DNA double-strand breaks in neurons, with exacerbation by amyloid-\u03b2","volume":"16","author":"Suberbielle","year":"2013","journal-title":"Nat. Neurosci."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1186\/s40478-019-0723-5","article-title":"Early neuronal accumulation of DNA double strand breaks in Alzheimer\u2019s disease","volume":"7","author":"Shanbhag","year":"2019","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"1175","DOI":"10.1038\/s42003-021-02671-4","article-title":"HMGB1 signaling phosphorylates Ku70 and impairs DNA damage repair in Alzheimer\u2019s disease pathology","volume":"4","author":"Tanaka","year":"2021","journal-title":"Commun. Biol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1016\/j.chembiol.2007.03.007","article-title":"Glycyrrhizin binds to high-mobility group box 1 protein and inhibits its cytokine activities","volume":"14","author":"Mollica","year":"2007","journal-title":"Chem. Biol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/j.nbd.2011.12.056","article-title":"Glycyrrhizic acid affords robust neuroprotection in the postischemic brain via anti-inflammatory effect by inhibiting HMGB1 phosphorylation and secretion","volume":"46","author":"Kim","year":"2012","journal-title":"Neurobiol. Dis."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1016\/j.intimp.2016.11.002","article-title":"Ethyl pyruvate inhibits the acetylation and release of HMGB1 via effects on SIRT1\/STAT signaling in LPS-activated RAW264.7 cells and peritoneal macrophages","volume":"41","author":"Kim","year":"2016","journal-title":"Int. Immunopharmacol."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"1039","DOI":"10.2119\/molmed.2010.00264","article-title":"Monoclonal anti-HMGB1 (high mobility group box chromosomal protein 1) antibody protection in two experimental arthritis models","volume":"17","author":"Schierbeck","year":"2011","journal-title":"Mol. Med."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1038\/s41419-018-0438-8","article-title":"Alarmin HMGB1 induces systemic and brain inflammatory exacerbation in post-stroke infection rat model","volume":"9","author":"Kim","year":"2018","journal-title":"Cell Death Dis."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"6413","DOI":"10.1523\/JNEUROSCI.3815-05.2006","article-title":"HMGB1, a novel cytokine-like mediator linking acute neuronal death and delayed neuroinflammation in the postischemic brain","volume":"26","author":"Kim","year":"2006","journal-title":"J. Neurosci."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/j.neulet.2012.07.040","article-title":"Intranasal delivery of HMGB1-binding heptamer peptide confers a robust neuroprotection in the postischemic brain","volume":"525","author":"Kim","year":"2012","journal-title":"Neurosci. Lett."},{"key":"ref_103","doi-asserted-by":"crossref","unstructured":"Zhu, X., Chen, C., Ye, D., Guan, D., Ye, L., Jin, J., Zhao, H., Chen, Y., Wang, Z., and Wang, X. (2012). Diammonium glycyrrhizinate upregulates PGC-1\u03b1 and protects against A\u03b21-42-induced neurotoxicity. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0035823"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/j.cytogfr.2024.07.004","article-title":"Deciphering the roles of the HMGB family in cancer: Insights from subcellular localization dynamics","volume":"78","author":"Jiang","year":"2024","journal-title":"Cytokine Growth Factor Rev."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/19\/8681\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T09:28:40Z","timestamp":1790760520000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/19\/8681"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,28]]},"references-count":104,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2026,10]]}},"alternative-id":["ijms27198681"],"URL":"https:\/\/doi.org\/10.3390\/ijms27198681","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,28]]}}}