{"id":"https://openalex.org/W7225823617","doi":"https://doi.org/10.1186/s12974-026-04109-2","title":"How the aging immune system fuels neurodegeneration: the role of immune cell exhaustion and immunosenescence","display_name":"How the aging immune system fuels neurodegeneration: the role of immune cell exhaustion and immunosenescence","publication_year":2026,"publication_date":"2026-11-11","ids":{"openalex":"https://openalex.org/W7225823617","doi":"https://doi.org/10.1186/s12974-026-04109-2"},"language":"en","primary_location":{"id":"doi:10.1186/s12974-026-04109-2","doi":"https://doi.org/10.1186/s12974-026-04109-2","is_oa":true,"landing_page_url":"https://doi.org/10.1186/s12974-026-04109-2","pdf_url":null,"source":{"id":"https://openalex.org/S199572710","display_name":"Journal of Neuroinflammation","issn_l":"1742-2094","issn":["1742-2094"],"is_oa":true,"is_in_doaj":true,"is_core":true,"listed_in":["cwts-core","doaj","dongbi-b","doyens","jufo-1","ki-jl-2","medline","norway-1","oarl","poland-100","russia-white-list-1","vabb-shw"],"host_organization":"https://openalex.org/P4310320256","host_organization_name":"BioMed Central","host_organization_lineage":["https://openalex.org/P4310320256","https://openalex.org/P4310319965"],"host_organization_lineage_names":["BioMed Central","Springer Nature"],"type":"journal"},"license":"cc-by","license_id":"https://openalex.org/licenses/cc-by","version":"publishedVersion","is_accepted":true,"is_published":true,"raw_source_name":"Journal of Neuroinflammation","raw_type":"journal-article"},"volume":null,"type":"article","is_traditional":true,"indexed_in":["crossref","doaj"],"open_access":{"is_oa":true,"oa_status":"gold","oa_url":"https://doi.org/10.1186/s12974-026-04109-2","any_repository_has_fulltext":false},"authorships":[{"author_position":"first","author":{"id":"https://openalex.org/A5034941377","display_name":"Rebecca L. Wallings","orcid":"https://orcid.org/0000-0003-0947-4459","observed_orcids":["https://orcid.org/0000-0003-0947-4459"]},"institutions":[{"id":"https://openalex.org/I4394709130","display_name":"Indiana University School of Medicine","ror":"https://ror.org/02ets8c94","country_code":"US","type":"education","lineage":["https://openalex.org/I4394709130","https://openalex.org/I592451"]}],"countries":["US"],"is_corresponding":true,"raw_author_name":"Rebecca L. Wallings","raw_affiliation_strings":["Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA","Department of Neurology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA","Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, 46202, USA"],"raw_orcid":null,"affiliations":[{"raw_affiliation_string":"Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA","institution_ids":["https://openalex.org/I4394709130"]},{"raw_affiliation_string":"Department of Neurology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA","institution_ids":["https://openalex.org/I4394709130"]},{"raw_affiliation_string":"Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, 46202, USA","institution_ids":["https://openalex.org/I4394709130"]}]},{"author_position":"middle","author":{"id":"https://openalex.org/A5108852891","display_name":"Samantha L. Lempke","orcid":null,"observed_orcids":[]},"institutions":[{"id":"https://openalex.org/I4394709130","display_name":"Indiana University School of Medicine","ror":"https://ror.org/02ets8c94","country_code":"US","type":"education","lineage":["https://openalex.org/I4394709130","https://openalex.org/I592451"]}],"countries":["US"],"is_corresponding":false,"raw_author_name":"Samantha L. Lempke","raw_affiliation_strings":["Department of Neurology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA","Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, 46202, USA"],"raw_orcid":null,"affiliations":[{"raw_affiliation_string":"Department of Neurology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA","institution_ids":["https://openalex.org/I4394709130"]},{"raw_affiliation_string":"Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, 46202, USA","institution_ids":["https://openalex.org/I4394709130"]}]},{"author_position":"middle","author":{"id":"https://openalex.org/A5052529763","display_name":"Julian R Mark","orcid":"https://orcid.org/0000-0003-4152-7725","observed_orcids":["https://orcid.org/0000-0003-4152-7725"]},"institutions":[{"id":"https://openalex.org/I2800717037","display_name":"University of Florida Health","ror":"https://ror.org/04tk2gy88","country_code":"US","type":"education","lineage":["https://openalex.org/I2800717037","https://openalex.org/I33213144"]},{"id":"https://openalex.org/I33213144","display_name":"University of Florida","ror":"https://ror.org/02y3ad647","country_code":"US","type":"education","lineage":["https://openalex.org/I33213144"]}],"countries":["US"],"is_corresponding":false,"raw_author_name":"Julian R. Mark","raw_affiliation_strings":["Center for Translational Research in Neurodegenerative Disease, University of Florida, College of Medicine, McKnight Brain Institute, Gainesville, FL, 32610, USA","Department of Neuroscience, University of Florida, College of Medicine, McKnight Brain Institute, Gainesville, FL, 32610, USA"],"raw_orcid":null,"affiliations":[{"raw_affiliation_string":"Center for Translational Research in Neurodegenerative Disease, University of Florida, College of Medicine, McKnight Brain Institute, Gainesville, FL, 32610, USA","institution_ids":["https://openalex.org/I2800717037","https://openalex.org/I33213144"]},{"raw_affiliation_string":"Department of Neuroscience, University of Florida, College of Medicine, McKnight Brain Institute, Gainesville, FL, 32610, USA","institution_ids":["https://openalex.org/I33213144"]}]},{"author_position":"middle","author":{"id":"https://openalex.org/A5035859489","display_name":"MacKenzie L. Bolen","orcid":"https://orcid.org/0000-0003-1973-3784","observed_orcids":["https://orcid.org/0000-0003-1973-3784"]},"institutions":[{"id":"https://openalex.org/I4210137306","display_name":"Stanford Medicine","ror":"https://ror.org/03mtd9a03","country_code":"US","type":"healthcare","lineage":["https://openalex.org/I4210137306","https://openalex.org/I97018004"]},{"id":"https://openalex.org/I97018004","display_name":"Stanford University","ror":"https://ror.org/00f54p054","country_code":"US","type":"education","lineage":["https://openalex.org/I97018004"]}],"countries":["US"],"is_corresponding":false,"raw_author_name":"MacKenzie L. Bolen","raw_affiliation_strings":["Department of Neurology and Neurological Sciences, Stanford University, School of Medicine, Stanford, CA, USA"],"raw_orcid":null,"affiliations":[{"raw_affiliation_string":"Department of Neurology and Neurological Sciences, Stanford University, School of Medicine, Stanford, CA, USA","institution_ids":["https://openalex.org/I4210137306","https://openalex.org/I97018004"]}]},{"author_position":"middle","author":{"id":"https://openalex.org/A5041079492","display_name":"Chi Gidley Weindel","orcid":"https://orcid.org/0000-0002-8063-7794","observed_orcids":["https://orcid.org/0000-0002-8063-7794","https://orcid.org/0000-0002-0068-193X"]},"institutions":[{"id":"https://openalex.org/I114832834","display_name":"Tulane University","ror":"https://ror.org/04vmvtb21","country_code":"US","type":"education","lineage":["https://openalex.org/I114832834"]}],"countries":["US"],"is_corresponding":false,"raw_author_name":"Chi G. Weindel","raw_affiliation_strings":["Department of Microbiology and Immunology, Tulane University School of Medicine, New Orleans, LA, USA"],"raw_orcid":null,"affiliations":[{"raw_affiliation_string":"Department of Microbiology and Immunology, Tulane University School of Medicine, New Orleans, LA, USA","institution_ids":["https://openalex.org/I114832834"]}]},{"author_position":"middle","author":{"id":"https://openalex.org/A5161436991","display_name":"Jordan M. Weddle","orcid":null,"observed_orcids":[]},"institutions":[{"id":"https://openalex.org/I4394709130","display_name":"Indiana University School of Medicine","ror":"https://ror.org/02ets8c94","country_code":"US","type":"education","lineage":["https://openalex.org/I4394709130","https://openalex.org/I592451"]}],"countries":["US"],"is_corresponding":false,"raw_author_name":"Jordan M. Weddle","raw_affiliation_strings":["Department of Neurology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA","Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, 46202, USA"],"raw_orcid":null,"affiliations":[{"raw_affiliation_string":"Department of Neurology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA","institution_ids":["https://openalex.org/I4394709130"]},{"raw_affiliation_string":"Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, 46202, USA","institution_ids":["https://openalex.org/I4394709130"]}]},{"author_position":"last","author":{"id":"https://openalex.org/A5157904963","display_name":"Mal\u00fa G\u00e1mez Tansey","orcid":null,"observed_orcids":[]},"institutions":[{"id":"https://openalex.org/I4394709130","display_name":"Indiana University School of Medicine","ror":"https://ror.org/02ets8c94","country_code":"US","type":"education","lineage":["https://openalex.org/I4394709130","https://openalex.org/I592451"]}],"countries":["US"],"is_corresponding":true,"raw_author_name":"Mal\u00fa G\u00e1mez Tansey","raw_affiliation_strings":["Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA","Department of Neurology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA","Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, 46202, USA"],"raw_orcid":null,"affiliations":[{"raw_affiliation_string":"Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA","institution_ids":["https://openalex.org/I4394709130"]},{"raw_affiliation_string":"Department of Neurology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA","institution_ids":["https://openalex.org/I4394709130"]},{"raw_affiliation_string":"Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, 46202, USA","institution_ids":["https://openalex.org/I4394709130"]}]}],"institutions":[],"countries_distinct_count":1,"institutions_distinct_count":6,"corresponding_author_ids":["https://openalex.org/A5034941377","https://openalex.org/A5157904963"],"corresponding_institution_ids":["https://openalex.org/I4394709130"],"apc_list":{"value":4090,"currency":"USD","value_usd":4090},"apc_paid":{"value":4090,"currency":"USD","value_usd":4090},"fwci":0.0,"has_fulltext":false,"cited_by_count":0,"citation_normalized_percentile":{"value":0.0,"is_in_top_1_percent":false,"is_in_top_10_percent":false},"cited_by_percentile_year":null,"biblio":{"volume":null,"issue":null,"first_page":null,"last_page":null},"is_retracted":false,"is_paratext":false,"is_xpac":false,"primary_topic":{"id":"https://openalex.org/T11266","display_name":"Neuroinflammation and Neurodegeneration Mechanisms","score":0.9955999851226807,"subfield":{"id":"https://openalex.org/subfields/2808","display_name":"Neurology"},"field":{"id":"https://openalex.org/fields/28","display_name":"Neuroscience"},"domain":{"id":"https://openalex.org/domains/1","display_name":"Life Sciences"}},"topics":[{"id":"https://openalex.org/T11266","display_name":"Neuroinflammation and Neurodegeneration Mechanisms","score":0.9955999851226807,"subfield":{"id":"https://openalex.org/subfields/2808","display_name":"Neurology"},"field":{"id":"https://openalex.org/fields/28","display_name":"Neuroscience"},"domain":{"id":"https://openalex.org/domains/1","display_name":"Life Sciences"}},{"id":"https://openalex.org/T10676","display_name":"Genetics, Aging, and Longevity in Model Organisms","score":0.00039999998989515007,"subfield":{"id":"https://openalex.org/subfields/1302","display_name":"Aging"},"field":{"id":"https://openalex.org/fields/13","display_name":"Biochemistry, Genetics and Molecular Biology"},"domain":{"id":"https://openalex.org/domains/1","display_name":"Life Sciences"}},{"id":"https://openalex.org/T10086","display_name":"Alzheimer's disease research and treatments","score":0.0003000000142492354,"subfield":{"id":"https://openalex.org/subfields/2804","display_name":"Cellular and Molecular Neuroscience"},"field":{"id":"https://openalex.org/fields/28","display_name":"Neuroscience"},"domain":{"id":"https://openalex.org/domains/1","display_name":"Life Sciences"}}],"keywords":[],"concepts":[{"id":"https://openalex.org/C8891405","wikidata":"https://www.wikidata.org/wiki/Q1059","display_name":"Immune system","level":2,"score":0.8475000262260437},{"id":"https://openalex.org/C2779056147","wikidata":"https://www.wikidata.org/wiki/Q1660191","display_name":"Immunosenescence","level":3,"score":0.8104000091552734},{"id":"https://openalex.org/C2776914184","wikidata":"https://www.wikidata.org/wiki/Q101991","display_name":"Inflammation","level":2,"score":0.669700026512146},{"id":"https://openalex.org/C87753298","wikidata":"https://www.wikidata.org/wiki/Q17157137","display_name":"Neuroinflammation","level":3,"score":0.667900025844574},{"id":"https://openalex.org/C203014093","wikidata":"https://www.wikidata.org/wiki/Q101929","display_name":"Immunology","level":1,"score":0.6507999897003174},{"id":"https://openalex.org/C2779134260","wikidata":"https://www.wikidata.org/wiki/Q12136","display_name":"Disease","level":2,"score":0.531000018119812},{"id":"https://openalex.org/C2776252253","wikidata":"https://www.wikidata.org/wiki/Q7663815","display_name":"Systemic inflammation","level":3,"score":0.47749999165534973},{"id":"https://openalex.org/C193419808","wikidata":"https://www.wikidata.org/wiki/Q1645075","display_name":"Acquired immune system","level":3,"score":0.4706999957561493},{"id":"https://openalex.org/C136449434","wikidata":"https://www.wikidata.org/wiki/Q428253","display_name":"Innate immune system","level":3,"score":0.4275999963283539},{"id":"https://openalex.org/C157081693","wikidata":"https://www.wikidata.org/wiki/Q21113934","display_name":"CCL18","level":4,"score":0.42719998955726624},{"id":"https://openalex.org/C169760540","wikidata":"https://www.wikidata.org/wiki/Q207011","display_name":"Neuroscience","level":1,"score":0.4147000014781952},{"id":"https://openalex.org/C201934248","wikidata":"https://www.wikidata.org/wiki/Q2492999","display_name":"Neuroimmunology","level":3,"score":0.4018000066280365},{"id":"https://openalex.org/C86803240","wikidata":"https://www.wikidata.org/wiki/Q420","display_name":"Biology","level":0,"score":0.3903000056743622},{"id":"https://openalex.org/C71924100","wikidata":"https://www.wikidata.org/wiki/Q11190","display_name":"Medicine","level":0,"score":0.38929998874664307},{"id":"https://openalex.org/C2780194698","wikidata":"https://www.wikidata.org/wiki/Q6005429","display_name":"Immune dysregulation","level":3,"score":0.3855000138282776},{"id":"https://openalex.org/C2776090121","wikidata":"https://www.wikidata.org/wiki/Q193529","display_name":"T cell","level":3,"score":0.35019999742507935},{"id":"https://openalex.org/C2779341262","wikidata":"https://www.wikidata.org/wiki/Q182581","display_name":"Immunity","level":3,"score":0.3400999903678894},{"id":"https://openalex.org/C2780130043","wikidata":"https://www.wikidata.org/wiki/Q192360","display_name":"Autoimmunity","level":3,"score":0.3264999985694885},{"id":"https://openalex.org/C2910239545","wikidata":"https://www.wikidata.org/wiki/Q3843811","display_name":"Immune Dysfunction","level":3,"score":0.3206000030040741},{"id":"https://openalex.org/C2777422395","wikidata":"https://www.wikidata.org/wiki/Q3149136","display_name":"Immunocompetence","level":3,"score":0.31150001287460327},{"id":"https://openalex.org/C127716648","wikidata":"https://www.wikidata.org/wiki/Q104053","display_name":"Phenotype","level":3,"score":0.30660000443458557},{"id":"https://openalex.org/C159674089","wikidata":"https://www.wikidata.org/wiki/Q6005582","display_name":"Immunotoxicology","level":3,"score":0.2930999994277954},{"id":"https://openalex.org/C16568411","wikidata":"https://www.wikidata.org/wiki/Q83042","display_name":"Neurology","level":2,"score":0.2784999907016754},{"id":"https://openalex.org/C2984863031","wikidata":"https://www.wikidata.org/wiki/Q83030","display_name":"Cognitive decline","level":4,"score":0.2768999934196472},{"id":"https://openalex.org/C2779830541","wikidata":"https://www.wikidata.org/wiki/Q1622829","display_name":"Microglia","level":3,"score":0.273499995470047},{"id":"https://openalex.org/C2778296632","wikidata":"https://www.wikidata.org/wiki/Q1550619","display_name":"Regulatory T cell","level":5,"score":0.2653000056743622},{"id":"https://openalex.org/C2777314012","wikidata":"https://www.wikidata.org/wiki/Q7799617","display_name":"Thymic involution","level":4,"score":0.26460000872612},{"id":"https://openalex.org/C522857546","wikidata":"https://www.wikidata.org/wiki/Q2070979","display_name":"Senescence","level":2,"score":0.26429998874664307},{"id":"https://openalex.org/C2777702733","wikidata":"https://www.wikidata.org/wiki/Q1356761","display_name":"Immune tolerance","level":3,"score":0.26339998841285706},{"id":"https://openalex.org/C2780640218","wikidata":"https://www.wikidata.org/wiki/Q8277","display_name":"Multiple sclerosis","level":2,"score":0.2621000111103058},{"id":"https://openalex.org/C47742525","wikidata":"https://www.wikidata.org/wiki/Q13418826","display_name":"Innate lymphoid cell","level":4,"score":0.2542000114917755}],"mesh":[],"locations_count":1,"locations":[{"id":"doi:10.1186/s12974-026-04109-2","doi":"https://doi.org/10.1186/s12974-026-04109-2","is_oa":true,"landing_page_url":"https://doi.org/10.1186/s12974-026-04109-2","pdf_url":null,"source":{"id":"https://openalex.org/S199572710","display_name":"Journal of Neuroinflammation","issn_l":"1742-2094","issn":["1742-2094"],"is_oa":true,"is_in_doaj":true,"is_core":true,"listed_in":["cwts-core","doaj","dongbi-b","doyens","jufo-1","ki-jl-2","medline","norway-1","oarl","poland-100","russia-white-list-1","vabb-shw"],"host_organization":"https://openalex.org/P4310320256","host_organization_name":"BioMed Central","host_organization_lineage":["https://openalex.org/P4310320256","https://openalex.org/P4310319965"],"host_organization_lineage_names":["BioMed Central","Springer Nature"],"type":"journal"},"license":"cc-by","license_id":"https://openalex.org/licenses/cc-by","version":"publishedVersion","is_accepted":true,"is_published":true,"raw_source_name":"Journal of Neuroinflammation","raw_type":"journal-article"}],"best_oa_location":{"id":"doi:10.1186/s12974-026-04109-2","doi":"https://doi.org/10.1186/s12974-026-04109-2","is_oa":true,"landing_page_url":"https://doi.org/10.1186/s12974-026-04109-2","pdf_url":null,"source":{"id":"https://openalex.org/S199572710","display_name":"Journal of Neuroinflammation","issn_l":"1742-2094","issn":["1742-2094"],"is_oa":true,"is_in_doaj":true,"is_core":true,"listed_in":["cwts-core","doaj","dongbi-b","doyens","jufo-1","ki-jl-2","medline","norway-1","oarl","poland-100","russia-white-list-1","vabb-shw"],"host_organization":"https://openalex.org/P4310320256","host_organization_name":"BioMed Central","host_organization_lineage":["https://openalex.org/P4310320256","https://openalex.org/P4310319965"],"host_organization_lineage_names":["BioMed Central","Springer Nature"],"type":"journal"},"license":"cc-by","license_id":"https://openalex.org/licenses/cc-by","version":"publishedVersion","is_accepted":true,"is_published":true,"raw_source_name":"Journal of Neuroinflammation","raw_type":"journal-article"},"sustainable_development_goals":[],"study_designs":[],"awards":[],"funders":[],"has_content":{"grobid_xml":false,"pdf":false},"content_urls":null,"referenced_works_count":0,"referenced_works":[],"related_works":[],"abstract_inverted_index":{"Abstract":[0],"Age-related":[1],"neurodegenerative":[2],"diseases":[3,180],"(ARNDs),":[4],"including":[5],"Alzheimer\u2019s":[6],"disease":[7,11,125],"(AD)":[8],"and":[9,44,54,63,74,79,84,90,101,105,114,132,138],"Parkinson\u2019s":[10],"(PD),":[12],"are":[13],"increasingly":[14],"recognized":[15],"as":[16,179,190],"disorders":[17],"involving":[18,129],"systemic":[19,46,107],"immune":[20,51,61,86,98,110,134,154,160,209],"dysfunction":[21],"in":[22,58,88],"addition":[23],"to":[24,67,124,194],"central":[25,85],"nervous":[26],"system":[27],"pathology.":[28],"While":[29],"chronic":[30,45,106],"neuroinflammation":[31],"is":[32],"a":[33,172,191],"well-established":[34],"hallmark":[35],"of":[36,97,159,181,188,202],"both":[37],"diseases,":[38],"emerging":[39],"evidence":[40,76,120,170],"suggests":[41,156],"that":[42,157,204],"aging":[43,104],"inflammation":[47,108,183],"may":[48,57,162],"ultimately":[49],"drive":[50],"cell":[52],"exhaustion":[53],"immunosenescence,":[55],"which":[56],"turn":[59],"impair":[60],"surveillance":[62],"protein":[64],"clearance,":[65],"contributing":[66],"progressive":[68,186],"neurodegeneration.":[69,166],"Here,":[70],"we":[71,142],"review":[72],"clinical":[73],"preclinical":[75],"supporting":[77],"exhaustion-":[78],"senescence-associated":[80],"phenotypes":[81],"across":[82],"peripheral":[83],"compartments":[87],"AD":[89],"PD.":[91],"We":[92,117],"first":[93],"outline":[94],"the":[95,168,200],"spectrum":[96],"activation":[99],"states":[100],"describe":[102],"how":[103],"remodel":[109],"function":[111],"toward":[112,184],"exhausted":[113],"senescent":[115],"states.":[116],"then":[118],"examine":[119],"linking":[121],"these":[122,144],"processes":[123],"progression,":[126],"highlighting":[127],"mechanisms":[128],"impaired":[130],"adaptive":[131],"innate":[133],"responses,":[135],"metabolic":[136],"dysfunction,":[137],"neuroimmune":[139],"crosstalk.":[140],"Finally,":[141],"contrast":[143],"findings":[145],"with":[146,196],"observations":[147],"from":[148,175],"cognitively":[149],"healthy":[150],"centenarians,":[151],"whose":[152],"preserved":[153],"competence":[155],"maintenance":[158],"fitness":[161],"promote":[163],"resilience":[164],"against":[165],"Collectively,":[167],"available":[169],"supports":[171],"conceptual":[173],"shift":[174],"viewing":[176],"ARNDs":[177],"solely":[178],"excessive":[182],"recognizing":[185],"loss":[187],"immunocompetence":[189],"key":[192],"contributor":[193],"pathogenesis,":[195],"important":[197],"implications":[198],"for":[199],"development":[201],"therapies":[203],"restore,":[205],"rather":[206],"than":[207],"suppress,":[208],"function.":[210]},"counts_by_year":[],"updated_date":"2026-11-12T12:28:57.059296","created_date":"2026-11-12T00:00:00"}