{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T16:03:00Z","timestamp":1789401780415,"version":"build-2803163510"},"reference-count":56,"publisher":"Springer Science and Business Media LLC","issue":"4","license":[{"start":{"date-parts":[[2025,11,14]],"date-time":"2025-11-14T00:00:00Z","timestamp":1763078400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,11,14]],"date-time":"2025-11-14T00:00:00Z","timestamp":1763078400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["RF1 AG064859"],"award-info":[{"award-number":["RF1 AG064859"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["T32 AG078110"],"award-info":[{"award-number":["T32 AG078110"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["P30 AG072946"],"award-info":[{"award-number":["P30 AG072946"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["P01AG078115"],"award-info":[{"award-number":["P01AG078115"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["R01AG070830"],"award-info":[{"award-number":["R01AG070830"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["RF1NS118558"],"award-info":[{"award-number":["RF1NS118558"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006312","name":"BrightFocus Foundation","doi-asserted-by":"publisher","award":["A2024039S"],"award-info":[{"award-number":["A2024039S"]}],"id":[{"id":"10.13039\/100006312","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["P20GM1483267"],"award-info":[{"award-number":["P20GM1483267"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["GeroScience"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    The p38 mitogen-activated protein kinase has a well-characterized role in modulation of inflammatory processes throughout the body. In the central nervous system, p38 is primarily studied within neurons and microglia, most commonly in the context of neurological insult. The present study was designed to determine its function in astrocytes during non-pathological aging. We generated a conditional knockout model in which a tamoxifen-inducible\n                    <jats:italic>Aldh1l1<\/jats:italic>\n                    promoter drives\n                    <jats:italic>Cre recombinase<\/jats:italic>\n                    expression in mice with exon 1 of the p38\u03b1 gene flanked by loxP sites. Knockout of astrocyte p38\u03b1 was achieved via tamoxifen administration in young sexually mature mice at 3\u20134\u00a0months old. Animals were subsequently aged to 21\u201324\u00a0months prior to performing electrophysiological, immunohistochemical, and biochemical analyses. We found that early loss of astrocyte p38\u03b1 was associated with a reduction in hippocampal neuroinflammation and concomitant enhancement of synaptic strength in aged female mice. In subsequent experiments in younger animals, the knockout reduced peripheral GFAP levels and increased non-synaptic mitochondrial uncoupling. These findings indicate that astrocyte p38\u03b1 has wide-ranging effects on brain metabolism, inflammation, and synaptic function during the course of normal aging, including release of GFAP from the central nervous system to the periphery. Follow-up studies exploring the role of astrocyte p38\u03b1 in various age-associated neuropathological contexts are warranted.\n                  <\/jats:p>","DOI":"10.1007\/s11357-025-01948-4","type":"journal-article","created":{"date-parts":[[2025,11,14]],"date-time":"2025-11-14T17:21:40Z","timestamp":1763140900000},"page":"6017-6030","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Early loss of astrocyte p38\u03b1 MAPK reduces hippocampal neuroinflammation, enhances synaptic strength, and increases non-synaptic mitochondrial uncoupling in female mice during non-pathological aging"],"prefix":"10.1007","volume":"48","author":[{"given":"Caleb S.","family":"Bailey","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John C.","family":"Gant","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hilaree N.","family":"Frazier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Josh M.","family":"Morganti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meggie C.","family":"Coleman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Verda A.","family":"Davis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hemendra","family":"J. Vekaria","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"G. Sullivan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher M.","family":"Norris","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linda J.","family":"Van Eldik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6967-0489","authenticated-orcid":false,"given":"David J.","family":"Braun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,11,14]]},"reference":[{"issue":"5","key":"1948_CR1","doi-asserted-by":"publisher","first-page":"346","DOI":"10.1038\/s41580-020-00322-w","volume":"22","author":"B Canovas","year":"2021","unstructured":"Canovas B, Nebreda AR. Diversity and versatility of p38 kinase signalling in health and disease. Nat Rev Mol Cell Biol. 2021;22(5):346\u201366.","journal-title":"Nat Rev Mol Cell Biol"},{"key":"1948_CR2","doi-asserted-by":"publisher","first-page":"570586","DOI":"10.3389\/fnmol.2020.570586","volume":"13","author":"PR Asih","year":"2020","unstructured":"Asih PR, Prikas E, Stefanoska K, Tan ARP, Ahel HI, Ittner A. Functions of p38 MAP kinases in the central nervous system. Front Mol Neurosci. 2020;13:570586.","journal-title":"Front Mol Neurosci"},{"key":"1948_CR3","doi-asserted-by":"publisher","first-page":"7405","DOI":"10.1038\/srep07405","volume":"4","author":"U Lo","year":"2014","unstructured":"Lo U, Selvaraj V, Plane JM, Chechneva OV, Otsu K, Deng W. p38alpha (MAPK14) critically regulates the immunological response and the production of specific cytokines and chemokines in astrocytes. Sci Rep. 2014;4:7405.","journal-title":"Sci Rep"},{"issue":"1","key":"1948_CR4","doi-asserted-by":"publisher","first-page":"2968","DOI":"10.1038\/s41467-019-10830-9","volume":"10","author":"M Navarrete","year":"2019","unstructured":"Navarrete M, Cuartero MI, Palenzuela R, Draffin JE, Konomi A, Serra I, et al. Astrocytic p38alpha MAPK drives NMDA receptor-dependent long-term depression and modulates long-term memory. Nat Commun. 2019;10(1):2968.","journal-title":"Nat Commun"},{"issue":"3","key":"1948_CR5","doi-asserted-by":"publisher","first-page":"957","DOI":"10.1046\/j.1471-4159.2001.00333.x","volume":"77","author":"P Derkinderen","year":"2001","unstructured":"Derkinderen P, Ledent C, Parmentier M, Girault JA. Cannabinoids activate p38 mitogen-activated protein kinases through CB1 receptors in hippocampus. J Neurochem. 2001;77(3):957\u201360.","journal-title":"J Neurochem"},{"issue":"5","key":"1948_CR6","doi-asserted-by":"publisher","first-page":"1039","DOI":"10.1016\/j.cell.2012.01.037","volume":"148","author":"J Han","year":"2012","unstructured":"Han J, Kesner P, Metna-Laurent M, Duan TT, Xu L, Georges F, et al. Acute cannabinoids impair working memory through astroglial CB receptor modulation of hippocampal LTD. Cell. 2012;148(5):1039\u201350.","journal-title":"Cell"},{"key":"1948_CR7","doi-asserted-by":"publisher","first-page":"148","DOI":"10.3389\/fnagi.2020.00148","volume":"12","author":"X Han","year":"2020","unstructured":"Han X, Zhang T, Liu H, Mi Y, Gou X. Astrocyte senescence and Alzheimer\u2019s disease: a review. Front Aging Neurosci. 2020;12:148.","journal-title":"Front Aging Neurosci"},{"key":"1948_CR8","doi-asserted-by":"crossref","unstructured":"Weber M, Wu T, Hanson JE, Alam NM, Solanoy H, Ngu H, et al. Cognitive deficits, changes in synaptic function, and brain pathology in a mouse model of normal aging(1,2,3). eNeuro. 2015;2(5).","DOI":"10.1523\/ENEURO.0047-15.2015"},{"issue":"5","key":"1948_CR9","doi-asserted-by":"publisher","first-page":"e0286495","DOI":"10.1371\/journal.pone.0286495","volume":"18","author":"DJ Braun","year":"2023","unstructured":"Braun DJ, Frazier HN, Davis VA, Coleman MJ, Rogers CB, Van Eldik LJ. Early chronic suppression of microglial p38alpha in a model of Alzheimer\u2019s disease does not significantly alter amyloid-associated neuropathology. PLoS ONE. 2023;18(5):e0286495.","journal-title":"PLoS ONE"},{"issue":"1","key":"1948_CR10","doi-asserted-by":"publisher","first-page":"98","DOI":"10.1186\/s12974-019-1493-5","volume":"16","author":"JM Morganti","year":"2019","unstructured":"Morganti JM, Goulding DS, Van Eldik LJ. Deletion of p38alpha MAPK in microglia blunts trauma-induced inflammatory responses in mice. J Neuroinflammation. 2019;16(1):98.","journal-title":"J Neuroinflammation"},{"key":"1948_CR11","doi-asserted-by":"publisher","first-page":"100826","DOI":"10.1016\/j.bbih.2024.100826","volume":"40","author":"HN Frazier","year":"2024","unstructured":"Frazier HN, Braun DJ, Bailey CS, Coleman MJ, Davis VA, Dundon SR, et al. A small molecule p38alpha MAPK inhibitor, MW150, attenuates behavioral deficits and neuronal dysfunction in a mouse model of mixed amyloid and vascular pathologies. Brain Behav Immun Health. 2024;40:100826.","journal-title":"Brain Behav Immun Health"},{"key":"1948_CR12","doi-asserted-by":"crossref","unstructured":"Mathis DM, Furman JL, Norris CM. Preparation of acute hippocampal slices from rats and transgenic mice for the study of synaptic alterations during aging and amyloid pathology. J Vis Exp. 2011(49).","DOI":"10.3791\/2330"},{"key":"1948_CR13","doi-asserted-by":"publisher","first-page":"1378536","DOI":"10.3389\/fmolb.2024.1378536","volume":"11","author":"HJ Vekaria","year":"2024","unstructured":"Vekaria HJ, Kalimon OJ, Prajapati P, Velmurugan GV, Sullivan PG. An efficient and high-throughput method for the evaluation of mitochondrial dysfunction in frozen brain samples after traumatic brain injury. Front Mol Biosci. 2024;11:1378536.","journal-title":"Front Mol Biosci"},{"issue":"1","key":"1948_CR14","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1186\/s12974-017-0920-8","volume":"14","author":"CA Mangold","year":"2017","unstructured":"Mangold CA, Wronowski B, Du M, Masser DR, Hadad N, Bixler GV, et al. Sexually divergent induction of microglial-associated neuroinflammation with hippocampal aging. J Neuroinflammation. 2017;14(1):141.","journal-title":"J Neuroinflammation"},{"key":"1948_CR15","doi-asserted-by":"publisher","first-page":"1416","DOI":"10.3389\/fimmu.2020.01416","volume":"11","author":"A Matejuk","year":"2020","unstructured":"Matejuk A, Ransohoff RM. Crosstalk between astrocytes and microglia: an overview. Front Immunol. 2020;11:1416.","journal-title":"Front Immunol"},{"issue":"36","key":"1948_CR16","doi-asserted-by":"publisher","first-page":"11929","DOI":"10.1523\/JNEUROSCI.1860-14.2014","volume":"34","author":"Y Zhang","year":"2014","unstructured":"Zhang Y, Chen K, Sloan SA, Bennett ML, Scholze AR, O\u2019Keeffe S, et al. An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex. J Neurosci. 2014;34(36):11929\u201347.","journal-title":"J Neurosci"},{"issue":"1","key":"1948_CR17","doi-asserted-by":"publisher","first-page":"5829","DOI":"10.1038\/s41467-024-49608-z","volume":"15","author":"RF Perez","year":"2024","unstructured":"Perez RF, Tezanos P, Penarroya A, Gonzalez-Ramon A, Urdinguio RG, Gancedo-Verdejo J, et al. A multiomic atlas of the aging hippocampus reveals molecular changes in response to environmental enrichment. Nat Commun. 2024;15(1):5829.","journal-title":"Nat Commun"},{"issue":"D1","key":"1948_CR18","doi-asserted-by":"publisher","first-page":"D638","DOI":"10.1093\/nar\/gkac1000","volume":"51","author":"D Szklarczyk","year":"2023","unstructured":"Szklarczyk D, Kirsch R, Koutrouli M, Nastou K, Mehryary F, Hachilif R, et al. The STRING database in 2023: protein-protein association networks and functional enrichment analyses for any sequenced genome of interest. Nucleic Acids Res. 2023;51(D1):D638\u201346.","journal-title":"Nucleic Acids Res"},{"issue":"2","key":"1948_CR19","doi-asserted-by":"publisher","first-page":"481","DOI":"10.3233\/JAD-180325","volume":"67","author":"P Oeckl","year":"2019","unstructured":"Oeckl P, Halbgebauer S, Anderl-Straub S, Steinacker P, Huss AM, Neugebauer H, et al. Glial fibrillary acidic protein in serum is increased in Alzheimer\u2019s disease and correlates with cognitive impairment. J Alzheimers Dis. 2019;67(2):481\u20138.","journal-title":"J Alzheimers Dis"},{"issue":"1","key":"1948_CR20","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1038\/s41398-020-01137-1","volume":"11","author":"P Chatterjee","year":"2021","unstructured":"Chatterjee P, Pedrini S, Stoops E, Goozee K, Villemagne VL, Asih PR, et al. Plasma glial fibrillary acidic protein is elevated in cognitively normal older adults at risk of Alzheimer\u2019s disease. Transl Psychiatry. 2021;11(1):27.","journal-title":"Transl Psychiatry"},{"key":"1948_CR21","doi-asserted-by":"publisher","first-page":"116307","DOI":"10.1016\/j.bcp.2024.116307","volume":"225","author":"NH Sarg","year":"2024","unstructured":"Sarg NH, Zaher DM, Abu Jayab NN, Mostafa SH, Ismail HH, Omar HA. The interplay of p38 MAPK signaling and mitochondrial metabolism, a dynamic target in cancer and pathological contexts. Biochem Pharmacol. 2024;225:116307.","journal-title":"Biochem Pharmacol"},{"issue":"4","key":"1948_CR22","doi-asserted-by":"publisher","first-page":"418","DOI":"10.1111\/jnc.14037","volume":"143","author":"A Grimm","year":"2017","unstructured":"Grimm A, Eckert A. Brain aging and neurodegeneration: from a mitochondrial point of view. J Neurochem. 2017;143(4):418\u201331.","journal-title":"J Neurochem"},{"issue":"12","key":"1948_CR23","doi-asserted-by":"publisher","first-page":"3788","DOI":"10.1093\/brain\/awab341","volume":"144","author":"WB Hubbard","year":"2021","unstructured":"Hubbard WB, Spry ML, Gooch JL, Cloud AL, Vekaria HJ, Burden S, et al. Clinically relevant mitochondrial-targeted therapy improves chronic outcomes after traumatic brain injury. Brain. 2021;144(12):3788\u2013807.","journal-title":"Brain"},{"issue":"1","key":"1948_CR24","doi-asserted-by":"publisher","first-page":"50","DOI":"10.1002\/ana.24020","volume":"75","author":"DN Krementsov","year":"2014","unstructured":"Krementsov DN, Noubade R, Dragon JA, Otsu K, Rincon M, Teuscher C. Sex-specific control of central nervous system autoimmunity by p38 mitogen-activated protein kinase signaling in myeloid cells. Ann Neurol. 2014;75(1):50\u201366.","journal-title":"Ann Neurol"},{"key":"1948_CR25","doi-asserted-by":"publisher","first-page":"577209","DOI":"10.1016\/j.jneuroim.2020.577209","volume":"342","author":"MM McGill","year":"2020","unstructured":"McGill MM, Sabikunnahar B, Fang Q, Teuscher C, Krementsov DN. The sex-specific role of p38 MAP kinase in CNS autoimmunity is regulated by estrogen receptor alpha. J Neuroimmunol. 2020;342:577209.","journal-title":"J Neuroimmunol"},{"key":"1948_CR26","doi-asserted-by":"publisher","first-page":"715311","DOI":"10.3389\/fimmu.2021.715311","volume":"12","author":"MM McGill","year":"2021","unstructured":"McGill MM, Richman AR, Boyd JR, Sabikunnahar B, Lahue KG, Montgomery TL, et al. P38 MAP kinase signaling in microglia plays a sex-specific protective role in CNS autoimmunity and regulates microglial transcriptional states. Front Immunol. 2021;12:715311.","journal-title":"Front Immunol"},{"key":"1948_CR27","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1016\/j.brainres.2011.02.045","volume":"1385","author":"S Yasuoka","year":"2011","unstructured":"Yasuoka S, Kawanokuchi J, Parajuli B, Jin S, Doi Y, Noda M, et al. Production and functions of IL-33 in the central nervous system. Brain Res. 2011;1385:8\u201317.","journal-title":"Brain Res"},{"issue":"1","key":"1948_CR28","doi-asserted-by":"publisher","first-page":"268","DOI":"10.1186\/s12974-020-01939-6","volume":"17","author":"F Reverchon","year":"2020","unstructured":"Reverchon F, de Concini V, Larrigaldie V, Benmerzoug S, Briault S, Togbe D, et al. Hippocampal interleukin-33 mediates neuroinflammation-induced cognitive impairments. J Neuroinflammation. 2020;17(1):268.","journal-title":"J Neuroinflammation"},{"issue":"8","key":"1948_CR29","doi-asserted-by":"publisher","first-page":"e1191","DOI":"10.1038\/tp.2017.176","volume":"7","author":"C Carlock","year":"2017","unstructured":"Carlock C, Wu J, Shim J, Moreno-Gonzalez I, Pitcher MR, Hicks J, et al. Interleukin33 deficiency causes tau abnormality and neurodegeneration with Alzheimer-like symptoms in aged mice. Transl Psychiatry. 2017;7(8):e1191.","journal-title":"Transl Psychiatry"},{"key":"1948_CR30","doi-asserted-by":"publisher","unstructured":"Wang Y, Fu WY, Cheung K, Hung KW, Chen C, Geng H, et al. Astrocyte-secreted IL-33 mediates homeostatic synaptic plasticity in the adult hippocampus. Proc Natl Acad Sci U S A. 2021. https:\/\/doi.org\/10.1073\/pnas.2020810118.","DOI":"10.1073\/pnas.2020810118"},{"key":"1948_CR31","doi-asserted-by":"publisher","first-page":"2531453","DOI":"10.1155\/2017\/2531453","volume":"2017","author":"T Nishizaki","year":"2017","unstructured":"Nishizaki T. IL-33 acts to express Schaffer collateral\/CA1 LTP and regulate learning and memory by targeting MyD88. Neural Plast. 2017;2017:2531453.","journal-title":"Neural Plast"},{"issue":"19","key":"1948_CR32","doi-asserted-by":"publisher","first-page":"E2705","DOI":"10.1073\/pnas.1604032113","volume":"113","author":"AK Fu","year":"2016","unstructured":"Fu AK, Hung KW, Yuen MY, Zhou X, Mak DS, Chan IC, et al. Il-33 ameliorates Alzheimer\u2019s disease-like pathology and cognitive decline. Proc Natl Acad Sci U S A. 2016;113(19):E2705-13.","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"1","key":"1948_CR33","doi-asserted-by":"publisher","first-page":"86","DOI":"10.1186\/s13195-020-00652-z","volume":"12","author":"CS Liang","year":"2020","unstructured":"Liang CS, Su KP, Tsai CL, Lee JT, Chu CS, Yeh TC, et al. The role of interleukin-33 in patients with mild cognitive impairment and Alzheimer\u2019s disease. Alzheimers Res Ther. 2020;12(1):86.","journal-title":"Alzheimers Res Ther"},{"issue":"1","key":"1948_CR34","doi-asserted-by":"publisher","first-page":"174","DOI":"10.1186\/s12974-020-01806-4","volume":"17","author":"M Saresella","year":"2020","unstructured":"Saresella M, Marventano I, Piancone F, La Rosa F, Galimberti D, Fenoglio C, et al. IL-33 and its decoy sST2 in patients with Alzheimer\u2019s disease and mild cognitive impairment. J Neuroinflammation. 2020;17(1):174.","journal-title":"J Neuroinflammation"},{"issue":"3","key":"1948_CR35","doi-asserted-by":"publisher","first-page":"973","DOI":"10.3233\/JAD-210026","volume":"80","author":"H Khodadadi","year":"2021","unstructured":"Khodadadi H, Salles EL, Jarrahi A, Costigliola V, Khan MB, Yu JC, et al. Cannabidiol ameliorates cognitive function via regulation of IL-33 and TREM2 upregulation in a murine model of Alzheimer\u2019s disease. J Alzheimers Dis. 2021;80(3):973\u20137.","journal-title":"J Alzheimers Dis"},{"key":"1948_CR36","doi-asserted-by":"publisher","first-page":"100941","DOI":"10.1016\/j.preteyeres.2021.100941","volume":"83","author":"DT Hass","year":"2021","unstructured":"Hass DT, Barnstable CJ. Uncoupling proteins in the mitochondrial defense against oxidative stress. Prog Retin Eye Res. 2021;83:100941.","journal-title":"Prog Retin Eye Res"},{"issue":"7\u20138","key":"1948_CR37","doi-asserted-by":"publisher","first-page":"463","DOI":"10.1016\/j.mad.2010.03.010","volume":"131","author":"SA Mookerjee","year":"2010","unstructured":"Mookerjee SA, Divakaruni AS, Jastroch M, Brand MD. Mitochondrial uncoupling and lifespan. Mech Ageing Dev. 2010;131(7\u20138):463\u201372.","journal-title":"Mech Ageing Dev"},{"issue":"6","key":"1948_CR38","doi-asserted-by":"publisher","first-page":"565","DOI":"10.1111\/j.1474-9726.2006.00252.x","volume":"5","author":"SS Ali","year":"2006","unstructured":"Ali SS, Xiong C, Lucero J, Behrens MM, Dugan LL, Quick KL. Gender differences in free radical homeostasis during aging: shorter-lived female C57BL6 mice have increased oxidative stress. Aging Cell. 2006;5(6):565\u201374.","journal-title":"Aging Cell"},{"key":"1948_CR39","doi-asserted-by":"publisher","first-page":"111182","DOI":"10.1016\/j.exger.2020.111182","volume":"145","author":"MM Bayliak","year":"2021","unstructured":"Bayliak MM, Sorochynska OM, Kuzniak OV, Gospodaryov DV, Demianchuk OI, Vasylyk YV, et al. Middle age as a turning point in mouse cerebral cortex energy and redox metabolism: modulation by every-other-day fasting. Exp Gerontol. 2021;145:111182.","journal-title":"Exp Gerontol"},{"issue":"1","key":"1948_CR40","doi-asserted-by":"publisher","first-page":"8528","DOI":"10.1038\/s41598-020-65402-5","volume":"10","author":"Y Wang","year":"2020","unstructured":"Wang Y, Shang Y, Mishra A, Bacon E, Yin F, Brinton R. Midlife chronological and endocrinological transitions in brain metabolism: system biology basis for increased Alzheimer\u2019s risk in female brain. Sci Rep. 2020;10(1):8528.","journal-title":"Sci Rep"},{"issue":"2","key":"1948_CR41","doi-asserted-by":"publisher","first-page":"R11","DOI":"10.1530\/JME-15-0146","volume":"55","author":"E Manieri","year":"2015","unstructured":"Manieri E, Sabio G. Stress kinases in the modulation of metabolism and energy balance. J Mol Endocrinol. 2015;55(2):R11-22.","journal-title":"J Mol Endocrinol"},{"issue":"45","key":"1948_CR42","doi-asserted-by":"publisher","first-page":"31014","DOI":"10.1074\/jbc.M114.570879","volume":"289","author":"H Perreten Lambert","year":"2014","unstructured":"Perreten Lambert H, Zenger M, Azarias G, Chatton JY, Magistretti PJ, Lengacher S. Control of mitochondrial pH by uncoupling protein 4 in astrocytes promotes neuronal survival. J Biol Chem. 2014;289(45):31014\u201328.","journal-title":"J Biol Chem"},{"issue":"23","key":"1948_CR43","doi-asserted-by":"publisher","first-page":"2303","DOI":"10.1016\/j.cub.2006.10.028","volume":"16","author":"S Li","year":"2006","unstructured":"Li S, Tian X, Hartley DM, Feig LA. The environment versus genetics in controlling the contribution of MAP kinases to synaptic plasticity. Curr Biol. 2006;16(23):2303\u201313.","journal-title":"Curr Biol"},{"issue":"46","key":"1948_CR44","doi-asserted-by":"publisher","first-page":"16129","DOI":"10.1523\/JNEUROSCI.2323-12.2012","volume":"32","author":"JL Furman","year":"2012","unstructured":"Furman JL, Sama DM, Gant JC, Beckett TL, Murphy MP, Bachstetter AD, et al. Targeting astrocytes ameliorates neurologic changes in a mouse model of Alzheimer\u2019s disease. J Neurosci. 2012;32(46):16129\u201340.","journal-title":"J Neurosci"},{"issue":"25","key":"1948_CR45","doi-asserted-by":"publisher","first-page":"6132","DOI":"10.1523\/JNEUROSCI.0877-17.2017","volume":"37","author":"P Sompol","year":"2017","unstructured":"Sompol P, Furman JL, Pleiss MM, Kraner SD, Artiushin IA, Batten SR, et al. Calcineurin\/NFAT signaling in activated astrocytes drives network hyperexcitability in Abeta-bearing mice. J Neurosci. 2017;37(25):6132\u201348.","journal-title":"J Neurosci"},{"issue":"10","key":"1948_CR46","doi-asserted-by":"publisher","first-page":"1797","DOI":"10.1523\/JNEUROSCI.1333-22.2023","volume":"43","author":"P Sompol","year":"2023","unstructured":"Sompol P, Gollihue JL, Weiss BE, Lin RL, Case SL, Kraner SD, et al. Targeting astrocyte signaling alleviates cerebrovascular and synaptic function deficits in a diet-based mouse model of small cerebral vessel disease. J Neurosci. 2023;43(10):1797\u2013813.","journal-title":"J Neurosci"},{"issue":"6","key":"1948_CR47","doi-asserted-by":"publisher","first-page":"364","DOI":"10.1016\/j.tins.2015.04.003","volume":"38","author":"Z Yang","year":"2015","unstructured":"Yang Z, Wang KK. Glial fibrillary acidic protein: from intermediate filament assembly and gliosis to neurobiomarker. Trends Neurosci. 2015;38(6):364\u201374.","journal-title":"Trends Neurosci"},{"key":"1948_CR48","doi-asserted-by":"publisher","first-page":"102","DOI":"10.1016\/j.neulet.2014.02.042","volume":"566","author":"W Boesmans","year":"2014","unstructured":"Boesmans W, Rocha NP, Reis HJ, Holt M, Vanden BP. The astrocyte marker Aldh1L1 does not reliably label enteric glial cells. Neurosci Lett. 2014;566:102\u20135.","journal-title":"Neurosci Lett"},{"issue":"3","key":"1948_CR49","doi-asserted-by":"publisher","first-page":"312","DOI":"10.1038\/s41593-020-00783-4","volume":"24","author":"C Escartin","year":"2021","unstructured":"Escartin C, Galea E, Lakatos A, O\u2019Callaghan JP, Petzold GC, Serrano-Pozo A, et al. Reactive astrocyte nomenclature, definitions, and future directions. Nat Neurosci. 2021;24(3):312\u201325.","journal-title":"Nat Neurosci"},{"key":"1948_CR50","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1016\/j.brainres.2014.01.013","volume":"1551","author":"G Roy Choudhury","year":"2014","unstructured":"Roy Choudhury G, Ryou MG, Poteet E, Wen Y, He R, Sun F, et al. Involvement of p38 MAPK in reactive astrogliosis induced by ischemic stroke. Brain Res. 2014;1551:45\u201358.","journal-title":"Brain Res"},{"issue":"11","key":"1948_CR51","doi-asserted-by":"publisher","first-page":"1540","DOI":"10.1093\/hmg\/ddn042","volume":"17","author":"G Tang","year":"2008","unstructured":"Tang G, Yue Z, Talloczy Z, Hagemann T, Cho W, Messing A, et al. Autophagy induced by Alexander disease-mutant GFAP accumulation is regulated by p38\/MAPK and mTOR signaling pathways. Hum Mol Genet. 2008;17(11):1540\u201355.","journal-title":"Hum Mol Genet"},{"key":"1948_CR52","doi-asserted-by":"crossref","unstructured":"Alam JJ, Koel\u2010Simmerlink MJA, Conway J, Verberk IMW, Teunissen C. Neflamapimod treatment reduces plasma glial fibriallary acidic protein levels in patients with pure dementia with Lewy bodies (DLB). Alzheimers Dement. 2024;20(Suppl 6).","DOI":"10.1002\/alz.091713"},{"key":"1948_CR53","doi-asserted-by":"publisher","first-page":"713077","DOI":"10.3389\/fnins.2021.713077","volume":"15","author":"F Beyer","year":"2021","unstructured":"Beyer F, Ludje W, Karpf J, Saher G, Beckervordersandforth R. Distribution of Aldh1L1-CreER(T2) recombination in astrocytes versus neural stem cells in the neurogenic niches of the adult mouse brain. Front Neurosci. 2021;15:713077.","journal-title":"Front Neurosci"},{"issue":"1","key":"1948_CR54","doi-asserted-by":"publisher","first-page":"106","DOI":"10.1186\/s13195-021-00843-2","volume":"13","author":"ND Prins","year":"2021","unstructured":"Prins ND, Harrison JE, Chu HM, Blackburn K, Alam JJ, Scheltens P. A phase 2 double-blind placebo-controlled 24-week treatment clinical study of the p38 alpha kinase inhibitor neflamapimod in mild Alzheimer\u2019s disease. Alzheimers Res Ther. 2021;13(1):106.","journal-title":"Alzheimers Res Ther"},{"issue":"4","key":"1948_CR55","doi-asserted-by":"publisher","first-page":"464","DOI":"10.1002\/acn3.549","volume":"5","author":"P Scheltens","year":"2018","unstructured":"Scheltens P, Prins N, Lammertsma A, Yaqub M, Gouw A, Wink AM, et al. An exploratory clinical study of p38alpha kinase inhibition in Alzheimer\u2019s disease. Ann Clin Transl Neurol. 2018;5(4):464\u201373.","journal-title":"Ann Clin Transl Neurol"},{"issue":"11","key":"1948_CR56","doi-asserted-by":"publisher","first-page":"5298","DOI":"10.1021\/acs.jmedchem.9b00058","volume":"62","author":"SM Roy","year":"2019","unstructured":"Roy SM, Minasov G, Arancio O, Chico LW, Van Eldik LJ, Anderson WF, et al. A Selective and brain penetrant p38alphaMAPK inhibitor candidate for neurologic and neuropsychiatric disorders that attenuates neuroinflammation and cognitive dysfunction. J Med Chem. 2019;62(11):5298\u2013311.","journal-title":"J Med Chem"}],"container-title":["GeroScience"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s11357-025-01948-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s11357-025-01948-4","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s11357-025-01948-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T15:07:07Z","timestamp":1789398427000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s11357-025-01948-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,14]]},"references-count":56,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["1948"],"URL":"https:\/\/doi.org\/10.1007\/s11357-025-01948-4","relation":{},"ISSN":["2509-2723"],"issn-type":[{"value":"2509-2723","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,14]]},"assertion":[{"value":"7 July 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 October 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 November 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","label":"Conflict of interest","group":{"name":"EthicsHeading","label":"Declarations"}}]}}