{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T21:58:14Z","timestamp":1793051894460,"version":"4.5.0"},"reference-count":126,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,2,19]],"date-time":"2025-02-19T00:00:00Z","timestamp":1739923200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000027","name":"National Institute on Alcohol Abuse and Alcoholism","doi-asserted-by":"publisher","award":["AA020024"],"award-info":[{"award-number":["AA020024"]}],"id":[{"id":"10.13039\/100000027","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000027","name":"National Institute on Alcohol Abuse and Alcoholism","doi-asserted-by":"publisher","award":["AA020023"],"award-info":[{"award-number":["AA020023"]}],"id":[{"id":"10.13039\/100000027","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000027","name":"National Institute on Alcohol Abuse and Alcoholism","doi-asserted-by":"publisher","award":["AA028924"],"award-info":[{"award-number":["AA028924"]}],"id":[{"id":"10.13039\/100000027","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["AG072894"],"award-info":[{"award-number":["AG072894"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Aging Neurosci."],"abstract":"<jats:p>Human studies suggest that heavy alcohol use may be an etiological factor contributing to the development of Alzheimer\u2019s disease (AD) neuropathology. Both alcohol use disorder (AUD) and AD share common underlying neuropathology, including proinflammatory high-mobility group box 1 (HMGB1)-mediated neuroimmune signaling and basal forebrain cholinergic neuron degeneration. Adolescent onset of binge drinking represents a significant risk factor for later development of an AUD, and accumulating evidence suggests that adolescent initiation of heavy alcohol use induces HMGB1 signaling and causes degeneration of the basal forebrain cholinergic system that persists into adulthood. However, it is unknown whether adolescent binge drinking confers increased risk for later development of AD-associated neuropathology through persistent induction of proinflammatory HMGB1 neuroimmune signaling. To investigate this question, we first (Experiment 1) assessed AD-associated neuropathology in the post-mortem human basal forebrain of individuals with AUD and an adolescent age of drinking onset relative to age-matched moderate drinking controls (CONs). In Experiment 2, we treated non-transgenic and 5xFAD male and female mice, which overexpress both mutant human APP and PS1, with adolescent intermittent ethanol (AIE; 5.0 g\/kg, i.g. 2-days on\/2-days off; postnatal day [P]30 \u2013 P55), and assessed AD-associated neuropathology in the adult (P100) basal forebrain. In Experiment 3, 5xFAD female mice received AIE treatment followed by glycyrrhizic acid (150 mg\/L), an HMGB1 inhibitor, in drinking water from P56 to P100, and basal forebrain tissue was collected on P100 for assessment of AD-associated neuropathology. In the post-mortem human AUD basal forebrain (Experiment 1), we report upregulation of <jats:italic>Hmgb1<\/jats:italic> and the HMGB1 receptors <jats:italic>Rage<\/jats:italic> and <jats:italic>Tlr4<\/jats:italic> as well as microglial activation and increased intraneuronal A\u03b2<jats:sub>1\u201342<\/jats:sub> accumulation in association with reduced cholinergic neuron marker expression (ChAT). In the 5xFAD mouse model (Experiment 2), AIE accelerated AD-associated induction of <jats:italic>Hmgb1<\/jats:italic> proinflammatory neuroimmune genes, microglial activation, and reductions of ChAT+ basal forebrain cholinergic neurons in the adult female, but not male, basal forebrain. In Experiment 3, post-AIE treatment with glycyrrhizic acid rescued the AIE-induced acceleration of AD-associated increases in proinflammatory HMGB1 neuroimmune signaling, microglial activation, and persistent reductions of basal forebrain cholinergic neurons in adult 5xFAD female mice. Together, these findings suggest that adolescent binge ethanol exposure may represent an underappreciated etiological factor contributing to onset of AD-associated neuropathology in adulthood through HMGB1- mediated neuroimmune signaling.<\/jats:p>","DOI":"10.3389\/fnagi.2025.1531628","type":"journal-article","created":{"date-parts":[[2025,2,19]],"date-time":"2025-02-19T06:53:01Z","timestamp":1739947981000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":16,"title":["Adolescent binge alcohol exposure accelerates Alzheimer\u2019s disease-associated basal forebrain neuropathology through proinflammatory HMGB1 signaling"],"prefix":"10.3389","volume":"17","author":[{"given":"Rachael P.","family":"Fisher","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lindsay","family":"Matheny","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarrah","family":"Ankeny","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liya","family":"Qin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr.","given":"Leon G.","family":"Coleman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan P.","family":"Vetreno","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,2,19]]},"reference":[{"key":"B1","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1007\/BF00697388","article-title":"Loss of neurons in the nucleus basalis of Meynert in Alzheimer\u2019s disease, paralysis agitans and Korsakoff\u2019s Disease.","volume":"61","author":"Arendt","year":"1983","journal-title":"Acta Neuropathol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"226","DOI":"10.1007\/BF00690530","article-title":"Amyloid deposition in the nucleus basalis of Meynert complex: A topographic marker for degenerating cell clusters in Alzheimer\u2019s disease.","volume":"75","author":"Arendt","year":"1988","journal-title":"Acta Neuropathol."},{"key":"B3","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1016\/j.mcna.2018.10.009","article-title":"The Alzheimer\u2019s disease clinical spectrum: Diagnosis and management.","volume":"103","author":"Atri","year":"2019","journal-title":"Med. Clin. North Am."},{"key":"B4","doi-asserted-by":"publisher","first-page":"215","DOI":"10.1159\/000487056","article-title":"Neuroinflammation in response to intracerebral injections of different HMGB1 redox isoforms.","volume":"10","author":"Aucott","year":"2018","journal-title":"J. Innate Immun."},{"key":"B5","doi-asserted-by":"crossref","first-page":"1722","DOI":"10.1093\/brain\/awv024","article-title":"Neuronal amyloid-beta accumulation within cholinergic basal forebrain in ageing and Alzheimer\u2019s disease.","volume":"138","author":"Baker-Nigh","year":"2015","journal-title":"Brain"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2022.884170","article-title":"Adolescent binge alcohol promotes early Alzheimer\u2019s disease pathology in adulthood through proinflammatory neuroimmune activation.","volume":"13","author":"Barnett","year":"2022","journal-title":"Front. Pharmacol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"308","DOI":"10.1093\/jnen\/59.4.308","article-title":"The cholinergic deficit coincides with Abeta deposition at the earliest histopathologic stages of Alzheimer disease.","volume":"59","author":"Beach","year":"2000","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"B8","doi-asserted-by":"crossref","first-page":"1077","DOI":"10.3233\/JAD-180141","article-title":"Differences between women and men in incidence rates of dementia and Alzheimer\u2019s disease.","volume":"64","author":"Beam","year":"2018","journal-title":"J. Alzheimers Dis."},{"key":"B9","doi-asserted-by":"publisher","first-page":"162","DOI":"10.1016\/j.neuroscience.2012.07.029","article-title":"Microglial activation in the injured and healthy brain: What are we really talking about? Practical and theoretical issues associated with the measurement of changes in microglial morphology.","volume":"225","author":"Beynon","year":"2012","journal-title":"Neuroscience"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.3389\/neuro.08.014.2009","article-title":"Early-life programming of later-life brain and behavior: A critical role for the immune system.","volume":"3","author":"Bilbo","year":"2009","journal-title":"Front. Behav. Neurosci."},{"key":"B11","doi-asserted-by":"publisher","first-page":"675","DOI":"10.1016\/j.neuron.2005.01.040","article-title":"Intraneuronal Abeta causes the onset of early Alzheimer\u2019s disease-related cognitive deficits in transgenic mice.","volume":"45","author":"Billings","year":"2005","journal-title":"Neuron"},{"key":"B12","doi-asserted-by":"crossref","first-page":"2849","DOI":"10.1097\/00001756-199709080-00009","article-title":"Nuclear translocation of NF-kappaB in cholinergic neurons of patients with Alzheimer\u2019s disease.","volume":"8","author":"Boissiere","year":"1997","journal-title":"Neuroreport"},{"key":"B13","doi-asserted-by":"publisher","first-page":"288","DOI":"10.1016\/j.neubiorev.2016.05.035","article-title":"Immunoadolescence: Neuroimmune development and adolescent behavior.","volume":"70","author":"Brenhouse","year":"2016","journal-title":"Neurosci. Biobehav. Rev."},{"key":"B14","doi-asserted-by":"crossref","first-page":"1219","DOI":"10.1016\/j.micinf.2004.08.004","article-title":"RAGE (receptor for advanced glycation end products): A central player in the inflammatory response.","volume":"6","author":"Chavakis","year":"2004","journal-title":"Microbes Infect."},{"key":"B15","doi-asserted-by":"publisher","first-page":"581","DOI":"10.1038\/nprot.2006.83","article-title":"The single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction: Twenty-something years on.","volume":"1","author":"Chomczynski","year":"2006","journal-title":"Nat. Protoc."},{"key":"B16","doi-asserted-by":"publisher","first-page":"142","DOI":"10.1016\/j.pbb.2013.11.021","article-title":"Adolescent binge ethanol treatment alters adult brain regional volumes, cortical extracellular matrix protein and behavioral flexibility.","volume":"116","author":"Coleman","year":"2014","journal-title":"Pharmacol. Biochem. Behav."},{"key":"B17","doi-asserted-by":"publisher","first-page":"671","DOI":"10.1111\/j.1530-0277.2010.01385.x","article-title":"Adolescent binge drinking alters adult brain neurotransmitter gene expression, behavior, brain regional volumes, and neurochemistry in mice.","volume":"35","author":"Coleman","year":"2011","journal-title":"Alcoholism Clin. Exp. Res."},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.3389\/fnmol.2022.992627","article-title":"Cholinergic REST-G9a gene repression through HMGB1-TLR4 neuroimmune signaling regulates basal forebrain cholinergic neuron phenotype.","volume":"15","author":"Crews","year":"2022","journal-title":"Front. Mol. Neurosci."},{"key":"B19","doi-asserted-by":"crossref","first-page":"1712","DOI":"10.1111\/j.1530-0277.2000.tb01973.x","article-title":"Binge ethanol consumption causes differential brain damage in young adolescent rats compared with adult rats.","volume":"24","author":"Crews","year":"2000","journal-title":"Alcohol. Clin. Exp. Res."},{"key":"B20","doi-asserted-by":"publisher","first-page":"5159","DOI":"10.1038\/s41380-023-02160-6","article-title":"HMGB1 neuroimmune signaling and REST-G9a gene repression contribute to ethanol-induced reversible suppression of the cholinergic neuron phenotype.","volume":"28","author":"Crews","year":"2023","journal-title":"Mol. Psychiatry"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.3389\/fnbeh.2021.652494","article-title":"Loss of basal forebrain cholinergic neurons following adolescent binge ethanol exposure: Recovery with the cholinesterase inhibitor galantamine.","volume":"15","author":"Crews","year":"2021","journal-title":"Front. Behav. Neurosci."},{"key":"B22","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1016\/j.alcohol.2004.04.005","article-title":"Exercise reverses ethanol inhibition of neural stem cell proliferation.","volume":"33","author":"Crews","year":"2004","journal-title":"Alcohol"},{"key":"B23","doi-asserted-by":"publisher","first-page":"602","DOI":"10.1016\/j.biopsych.2012.09.030","article-title":"High mobility group box 1\/Toll-like receptor danger signaling increases brain neuroimmune activation in alcohol dependence.","volume":"73","author":"Crews","year":"2013","journal-title":"Biol. Psychiatry"},{"key":"B24","doi-asserted-by":"crossref","first-page":"1806","DOI":"10.1111\/acer.14154","article-title":"Mechanisms of persistent neurobiological changes following adolescent alcohol exposure: NADIA consortium findings.","volume":"43","author":"Crews","year":"2019","journal-title":"Alcohol. Clin. Exp. Res."},{"key":"B25","doi-asserted-by":"crossref","first-page":"1483","DOI":"10.1007\/s00213-017-4560-6","article-title":"Toll-like receptor signaling and stages of addiction.","volume":"234","author":"Crews","year":"2017","journal-title":"Psychopharmacology (Berl)"},{"key":"B26","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1016\/j.pbb.2006.12.001","article-title":"Adolescent cortical development: A critical period of vulnerability for addiction.","volume":"86","author":"Crews","year":"2007","journal-title":"Pharmacol. Biochem. Behav."},{"key":"B27","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1016\/s0197-4580(98)00066-9","article-title":"Neurofibrillary degeneration and cell loss in the nucleus basalis in comparison to cortical Alzheimer pathology.","volume":"19","author":"Cullen","year":"1998","journal-title":"Neurobiol. Aging"},{"key":"B28","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1007\/s00702-017-1831-7","article-title":"Neuroinflammatory responses in Alzheimer\u2019s disease.","volume":"125","author":"Dansokho","year":"2018","journal-title":"J. Neural Transm."},{"key":"B29","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1111\/j.1530-0277.2000.tb04596.x","article-title":"Adolescents are not adults: Developmental considerations in alcohol users.","volume":"24","author":"Deas","year":"2000","journal-title":"Alcohol. Clin. Exp. Res."},{"key":"B30","doi-asserted-by":"publisher","first-page":"366","DOI":"10.3390\/ijms10010366","article-title":"The importance of brain banks for molecular neuropathological research: The New South wales tissue resource centre experience.","volume":"10","author":"Dedova","year":"2009","journal-title":"Int. J. Mol. Sci."},{"key":"B31","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1007\/s00401-006-0115-3","article-title":"RAGE, LRP-1, and amyloid-beta protein in Alzheimer\u2019s disease.","volume":"112","author":"Donahue","year":"2006","journal-title":"Acta Neuropathol."},{"key":"B32","doi-asserted-by":"publisher","first-page":"333","DOI":"10.1016\/j.neuroscience.2011.10.011","article-title":"Periadolescent ethanol exposure reduces adult forebrain ChAT+IR neurons: Correlation with behavioral pathology.","volume":"199","author":"Ehlers","year":"2011","journal-title":"Neuroscience"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1186\/1750-1326-8-2","article-title":"Neuron loss in the 5XFAD mouse model of Alzheimer\u2019s disease correlates with intraneuronal Abeta42 accumulation and Caspase-3 activation.","volume":"8","author":"Eimer","year":"2013","journal-title":"Mol. Neurodegener."},{"key":"B34","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/j.neuroscience.2017.08.013","article-title":"Adolescent binge ethanol exposure alters specific forebrain cholinergic cell populations and leads to selective functional deficits in the prefrontal cortex.","volume":"361","author":"Fernandez","year":"2017","journal-title":"Neuroscience"},{"key":"B35","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1038\/s41582-018-0032-9","article-title":"Sex differences in Alzheimer disease - The gateway to precision medicine.","volume":"14","author":"Ferretti","year":"2018","journal-title":"Nat. Rev. Neurol."},{"key":"B36","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1002\/ana.410330306","article-title":"Risk factors for late-onset Alzheimer\u2019s disease: A population-based, case-control study.","volume":"33","author":"Fratiglioni","year":"1993","journal-title":"Ann. Neurol."},{"key":"B37","doi-asserted-by":"publisher","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":"B38","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1007\/s00401-010-0679-9","article-title":"Intraneuronal beta-amyloid accumulation and synapse pathology in Alzheimer\u2019s disease.","volume":"119","author":"Gouras","year":"2010","journal-title":"Acta Neuropathol."},{"key":"B39","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/S0899-3289(97)90009-2","article-title":"Age at onset of alcohol use and its association with DSM-IV alcohol abuse and dependence: Results from the national longitudinal alcohol epidemiologic survey.","volume":"9","author":"Grant","year":"1997","journal-title":"J. Subst Abuse"},{"key":"B40","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/S0899-3289(99)80131-X","article-title":"Age of onset of drug use and its association with DSM-IV drug abuse and dependence: Results from the national longitudinal alcohol epidemiologic survey.","volume":"10","author":"Grant","year":"1998","journal-title":"J. Substance Abuse"},{"key":"B41","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1016\/s0899-3289(01)00096-7","article-title":"Age at onset of alcohol use and DSM-IV alcohol abuse and dependence: A 12-year follow-up.","volume":"13","author":"Grant","year":"2001","journal-title":"J Subst Abuse"},{"key":"B42","doi-asserted-by":"publisher","first-page":"805","DOI":"10.1016\/j.biopsych.2011.06.019","article-title":"Atrophy of the cholinergic Basal forebrain over the adult age range and in early stages of Alzheimer\u2019s disease.","volume":"71","author":"Grothe","year":"2012","journal-title":"Biol. Psychiatry"},{"key":"B43","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1016\/j.jalz.2008.04.005","article-title":"Basal forebrain atrophy is a presymptomatic marker for Alzheimer\u2019s disease.","volume":"4","author":"Hall","year":"2008","journal-title":"Alzheimers Dement."},{"key":"B44","doi-asserted-by":"crossref","first-page":"1917","DOI":"10.1093\/brain\/awy132","article-title":"The cholinergic system in the pathophysiology and treatment of Alzheimer\u2019s disease.","volume":"141","author":"Hampel","year":"2018","journal-title":"Brain"},{"key":"B45","doi-asserted-by":"crossref","first-page":"1504","DOI":"10.1002\/glia.23277","article-title":"Generation of a microglial developmental index in mice and in humans reveals a sex difference in maturation and immune reactivity.","volume":"66","author":"Hanamsagar","year":"2018","journal-title":"Glia"},{"key":"B46","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1083\/jcb.201709069","article-title":"Microglia in Alzheimer\u2019s disease.","volume":"217","author":"Hansen","year":"2018","journal-title":"J. Cell Biol."},{"key":"B47","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1016\/j.expneurol.2007.11.017","article-title":"Increased MCP-1 and microglia in various regions of the human alcoholic brain.","volume":"210","author":"He","year":"2008","journal-title":"Exp. Neurol."},{"key":"B48","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1016\/S1474-4422(15)70016-5","article-title":"Neuroinflammation in Alzheimer\u2019s disease.","volume":"14","author":"Heneka","year":"2015","journal-title":"Lancet Neurol."},{"key":"B49","doi-asserted-by":"crossref","first-page":"1356","DOI":"10.2174\/1567205013666160603005035","article-title":"The association between alcohol use and the progression of Alzheimer\u2019s disease.","volume":"13","author":"Heymann","year":"2016","journal-title":"Curr. Alzheimer Res."},{"key":"B50","first-page":"181","article-title":"Male and female sensitivity to alcohol-induced brain damage","volume":"27","author":"Hommer","year":"2003","journal-title":"Alcohol Res. Health"},{"key":"B51","doi-asserted-by":"publisher","first-page":"257","DOI":"10.1258\/rsmmsl.49.4.257","article-title":"Concentration distributions of the drugs most frequently identified in post-mortem femoral blood representing all causes of death.","volume":"49","author":"Jones","year":"2009","journal-title":"Med. Sci. Law"},{"key":"B52","first-page":"575","article-title":"Inflammation as a central mechanism in Alzheimer\u2019s disease.","volume":"4","author":"Kinney","year":"2018","journal-title":"Alzheimers Dement."},{"key":"B53","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1038\/nrn2168","article-title":"Intracellular amyloid-beta in Alzheimer\u2019s disease.","volume":"8","author":"LaFerla","year":"2007","journal-title":"Nat. Rev. Neurosci."},{"key":"B54","doi-asserted-by":"publisher","first-page":"1049","DOI":"10.1007\/s10654-015-0029-2","article-title":"Alcohol consumption and risk of dementia up to 27 years later in a large, population-based sample: The HUNT study Norway.","volume":"30","author":"Langballe","year":"2015","journal-title":"Eur. J. Epidemiol."},{"key":"B55","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1002\/cne.903300103","article-title":"Heterogeneity and selectivity of the degeneration of cholinergic neurons in the basal forebrain of patients with Alzheimer\u2019s disease.","volume":"330","author":"Lehericy","year":"1993","journal-title":"J. Comp. Neurol."},{"key":"B56","doi-asserted-by":"publisher","first-page":"157","DOI":"10.1038\/s41582-020-00435-y","article-title":"Neuroinflammation and microglial activation in Alzheimer disease: Where do we go from here?","volume":"17","author":"Leng","year":"2021","journal-title":"Nat. Rev. Neurol."},{"key":"B57","article-title":"NF-kappaB signaling in inflammation.","volume":"2","author":"Liu","year":"2017","journal-title":"Signal Transduct. Target Ther."},{"key":"B58","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1016\/j.cell.2019.09.001","article-title":"Alzheimer disease: An update on pathobiology and treatment strategies.","volume":"179","author":"Long","year":"2019","journal-title":"Cell"},{"key":"B59","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1006\/exnr.2001.7732","article-title":"Involvement of microglial receptor for advanced glycation endproducts (RAGE) in Alzheimer\u2019s disease: Identification of a cellular activation mechanism.","volume":"171","author":"Lue","year":"2001","journal-title":"Exp. Neurol."},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-021-02243-7","article-title":"Galantamine prevents and reverses neuroimmune induction and loss of adult hippocampal neurogenesis following adolescent alcohol exposure.","volume":"18","author":"Macht","year":"2021","journal-title":"J. Neuroinflammation"},{"key":"B61","doi-asserted-by":"publisher","first-page":"470","DOI":"10.1111\/acer.15019","article-title":"Indomethacin restores loss of hippocampal neurogenesis and cholinergic innervation and reduces innate immune expression and reversal learning deficits in adult male and female rats following adolescent ethanol exposure.","volume":"47","author":"Macht","year":"2023","journal-title":"Alcohol. Clin. Exp. Res."},{"key":"B62","doi-asserted-by":"publisher","first-page":"413","DOI":"10.1038\/nm.2127","article-title":"Toll-like receptor 4 and high-mobility group box-1 are involved in ictogenesis and can be targeted to reduce seizures.","volume":"16","author":"Maroso","year":"2010","journal-title":"Nat. Med."},{"key":"B63","doi-asserted-by":"publisher","first-page":"130","DOI":"10.1016\/0012-1606(74)90196-1","article-title":"Development of cholinergic innervation in the hippocampal formation of the rat. I. Histochemical demonstration of acetylcholinesterase activity.","volume":"36","author":"Matthews","year":"1974","journal-title":"Dev. Biol."},{"key":"B64","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1016\/j.conb.2013.01.024","article-title":"Neuroimmune signaling: A key component of alcohol abuse.","volume":"23","author":"Mayfield","year":"2013","journal-title":"Curr. Opin. Neurobiol."},{"key":"B65","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1212\/WNL.34.6.741","article-title":"Aging, Alzheimer\u2019s disease, and the cholinergic system of the basal forebrain.","volume":"34","author":"McGeer","year":"1984","journal-title":"Neurology"},{"key":"B66","doi-asserted-by":"publisher","first-page":"1908","DOI":"10.1111\/acer.14694","article-title":"Primed for addiction: A critical review of the role of microglia in the neurodevelopmental consequences of adolescent alcohol drinking.","volume":"45","author":"Melbourne","year":"2021","journal-title":"Alcohol. Clin. Exp. Res."},{"key":"B67","doi-asserted-by":"publisher","first-page":"1185","DOI":"10.1016\/0306-4522(83)90108-2","article-title":"Central cholinergic pathways in the rat: An overview based on an alternative nomenclature (Ch1-Ch6).","volume":"10","author":"Mesulam","year":"1983","journal-title":"Neuroscience"},{"key":"B68","doi-asserted-by":"publisher","first-page":"1547","DOI":"10.3233\/JAD-171160","article-title":"TLR4 gene expression and pro-inflammatory cytokines in Alzheimer\u2019s disease and in response to hippocampal deafferentation in rodents.","volume":"63","author":"Miron","year":"2018","journal-title":"J. Alzheimers Dis."},{"key":"B69","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":"B70","doi-asserted-by":"crossref","first-page":"1405","DOI":"10.1001\/jama.289.11.1405","article-title":"Prospective study of alcohol consumption and risk of dementia in older adults.","volume":"289","author":"Mukamal","year":"2003","journal-title":"JAMA"},{"key":"B71","doi-asserted-by":"publisher","first-page":"142","DOI":"10.1016\/0012-1606(74)90197-3","article-title":"Development of cholinergic innervation in the hippocampal formation of the rat. II. Quantitative changes in choline acetyltransferase and acetylcholinesterase activities.","volume":"36","author":"Nadler","year":"1974","journal-title":"Dev. Biol."},{"key":"B72","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1016\/0304-3940(83)90264-1","article-title":"Choline acetyltransferase immunohistochemistry in brains of Alzheimer\u2019s disease patients and controls.","volume":"36","author":"Nagai","year":"1983","journal-title":"Neurosci Lett"},{"key":"B73","year":"2020","journal-title":"Center for Behavioral Health Statistics and Quality."},{"key":"B74","doi-asserted-by":"publisher","first-page":"275","DOI":"10.1007\/s12640-015-9579-z","article-title":"Glycyrrhizic acid attenuates neuroinflammation and oxidative stress in rotenone model of Parkinson\u2019s disease.","volume":"29","author":"Ojha","year":"2016","journal-title":"Neurotox Res."},{"key":"B75","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1016\/j.tins.2011.02.005","article-title":"Toll-like receptor signaling in neural plasticity and disease.","volume":"34","author":"Okun","year":"2011","journal-title":"Trends Neurosci."},{"key":"B76","doi-asserted-by":"crossref","first-page":"3916","DOI":"10.4049\/jimmunol.173.6.3916","article-title":"Microglia initiate central nervous system innate and adaptive immune responses through multiple TLRs.","volume":"173","author":"Olson","year":"2004","journal-title":"J. Immunol."},{"key":"B77","doi-asserted-by":"publisher","first-page":"1130","DOI":"10.1111\/adb.12543","article-title":"Young alcohol binge drinkers have elevated blood endotoxin, peripheral inflammation and low cortisol levels: Neuropsychological correlations in women.","volume":"23","author":"Orio","year":"2018","journal-title":"Addict. Biol."},{"key":"B78","doi-asserted-by":"crossref","first-page":"6853","DOI":"10.1038\/sj.onc.1203239","article-title":"Activators and target genes of Rel\/NF-kappaB transcription factors.","volume":"18","author":"Pahl","year":"1999","journal-title":"Oncogene"},{"key":"B79","doi-asserted-by":"publisher","first-page":"1019","DOI":"10.1001\/jamapediatrics.2013.2392","article-title":"Extreme binge drinking among 12th-grade students in the United States: Prevalence and predictors.","volume":"167","author":"Patrick","year":"2013","journal-title":"JAMA Pediatr."},{"key":"B80","doi-asserted-by":"publisher","DOI":"10.3390\/cells9020383","article-title":"Impact of HMGB1, RAGE, and TLR4 in Alzheimer\u2019s disease (AD): From risk factors to therapeutic targeting.","volume":"9","author":"Paudel","year":"2020","journal-title":"Cells"},{"key":"B81","author":"Paxinos","year":"2019","journal-title":"The Mouse Brain in Stereotaxic Coordinates."},{"key":"B82","doi-asserted-by":"publisher","DOI":"10.1186\/1742-2094-9-130","article-title":"Chronic ethanol increases systemic TLR3 agonist-induced neuroinflammation and neurodegeneration.","volume":"9","author":"Qin","year":"2012","journal-title":"J. Neuroinflammation"},{"key":"B83","doi-asserted-by":"publisher","DOI":"10.1186\/1742-2094-5-10","article-title":"Increased systemic and brain cytokine production and neuroinflammation by endotoxin following ethanol treatment.","volume":"5","author":"Qin","year":"2008","journal-title":"J. Neuroinflammation"},{"key":"B84","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1002\/glia.20467","article-title":"Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration.","volume":"55","author":"Qin","year":"2007","journal-title":"Glia"},{"key":"B85","doi-asserted-by":"crossref","first-page":"1140","DOI":"10.2174\/1567205014666170203141717","article-title":"Neuroinflammation and Alzheimer\u2019s disease: Implications for microglial activation.","volume":"14","author":"Regen","year":"2017","journal-title":"Curr. Alzheimer Res."},{"key":"B86","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1016\/j.jsbmb.2016.03.012","article-title":"Age, APOE and sex: Triad of risk of Alzheimer\u2019s disease","volume":"160","author":"Riedel","year":"2016","journal-title":"J. Steroid Biochem. Mol. Biol"},{"key":"B87","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1002\/ana.410190502","article-title":"Epidemiology of clinically diagnosed Alzheimer\u2019s disease.","volume":"19","author":"Rocca","year":"1986","journal-title":"Ann. Neurol."},{"key":"B88","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1016\/S2352-4642(18)30022-1","article-title":"The age of adolescence.","volume":"2","author":"Sawyer","year":"2018","journal-title":"Lancet Child Adolesc. Health"},{"key":"B89","doi-asserted-by":"publisher","first-page":"1930","DOI":"10.1002\/glia.22409","article-title":"Toll-like receptor activation reveals developmental reorganization and unmasks responder subsets of microglia.","volume":"60","author":"Scheffel","year":"2012","journal-title":"Glia"},{"key":"B90","doi-asserted-by":"crossref","first-page":"225","DOI":"10.14283\/jpad.2018.34","article-title":"Female sex and Alzheimer\u2019s risk: The menopause connection","volume":"5","author":"Scheyer","year":"2018","journal-title":"J. Prev. Alzheimers Dis"},{"key":"B91","doi-asserted-by":"crossref","DOI":"10.1038\/ncomms13249","article-title":"Basal forebrain degeneration precedes and predicts the cortical spread of Alzheimer\u2019s pathology.","volume":"7","author":"Schmitz","year":"2016","journal-title":"Nat. Commun."},{"key":"B92","doi-asserted-by":"publisher","first-page":"17835","DOI":"10.1523\/JNEUROSCI.3297-11.2011","article-title":"Early-life experience decreases drug-induced reinstatement of morphine CPP in adulthood via microglial-specific epigenetic programming of anti-inflammatory IL-10 expression.","volume":"31","author":"Schwarz","year":"2011","journal-title":"J. Neurosci."},{"key":"B93","doi-asserted-by":"crossref","first-page":"948","DOI":"10.1111\/j.1471-4159.2011.07630.x","article-title":"Sex differences in microglial colonization of the developing rat brain.","volume":"120","author":"Schwarz","year":"2012","journal-title":"J. Neurochem."},{"key":"B94","doi-asserted-by":"publisher","first-page":"e124","DOI":"10.1016\/S2468-2667(18)30022-7","article-title":"Contribution of alcohol use disorders to the burden of dementia in France 2008-13: A nationwide retrospective cohort study.","volume":"3","author":"Schwarzinger","year":"2018","journal-title":"Lancet Public Health"},{"key":"B95","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1016\/s0079-6123(03)45001-2","article-title":"Phylogenetic and ontogenetic aspects of the basal forebrain cholinergic neurons and their innervation of the cerebral cortex.","volume":"145","author":"Semba","year":"2004","journal-title":"Prog. Brain Res."},{"key":"B96","doi-asserted-by":"publisher","first-page":"205","DOI":"10.1007\/s10561-008-9076-1","article-title":"An Australian brain bank: A critical investment with a high return!","volume":"9","author":"Sheedy","year":"2008","journal-title":"Cell Tissue Bank"},{"key":"B97","doi-asserted-by":"publisher","first-page":"1123","DOI":"10.1016\/j.euroneuro.2014.02.009","article-title":"Transitions in the transcriptome of the serotonergic and dopaminergic systems in the human brain during adolescence.","volume":"24","author":"Shoval","year":"2014","journal-title":"Eur. Neuropsychopharmacol."},{"key":"B98","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1016\/j.neuroscience.2004.12.037","article-title":"Orexin-saporin lesions of the medial septum impair spatial memory.","volume":"132","author":"Smith","year":"2005","journal-title":"Neuroscience"},{"key":"B99","author":"Spear","year":"2009","journal-title":"The Behavioral Neuroscience of Adolescence."},{"key":"B100","first-page":"1","article-title":"Cholinergic degeneration in early stages of Alzheimer\u2019s disease: Loss of cholinergic phenotype or loss of cells?","volume":"1","author":"Stepanichev","year":"2017","journal-title":"Alzheimer\u2019s Dement. Cogn. Neurol."},{"key":"B101","doi-asserted-by":"publisher","first-page":"2550","DOI":"10.1002\/glia.23510","article-title":"Microglial activation occurs late during preclinical Alzheimer\u2019s disease.","volume":"66","author":"Streit","year":"2018","journal-title":"Glia"},{"key":"B102","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0140042","article-title":"Adolescent intermittent alcohol exposure: Deficits in object recognition memory and forebrain cholinergic markers.","volume":"10","author":"Swartzwelder","year":"2015","journal-title":"PLoS One"},{"key":"B103","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1111\/pin.12520","article-title":"Plaque formation and the intraneuronal accumulation of beta-amyloid in Alzheimer\u2019s disease.","volume":"67","author":"Takahashi","year":"2017","journal-title":"Pathol. Int."},{"key":"B104","doi-asserted-by":"publisher","first-page":"1360","DOI":"10.2119\/molmed.2012.00314","article-title":"A Janus tale of two active high mobility group box 1 (HMGB1) redox states.","volume":"18","author":"Tang","year":"2012","journal-title":"Mol. Med."},{"key":"B105","doi-asserted-by":"publisher","first-page":"1349","DOI":"10.1002\/hbm.21111","article-title":"The cholinergic system in mild cognitive impairment and Alzheimer\u2019s disease: An in vivo MRI and DTI study.","volume":"32","author":"Teipel","year":"2011","journal-title":"Hum. Brain Mapp."},{"key":"B106","doi-asserted-by":"publisher","first-page":"1615","DOI":"10.2174\/1871527313666140806144831","article-title":"Receptor for AGEs (RAGE) as mediator of NF-kB pathway activation in neuroinflammation and oxidative stress.","volume":"13","author":"Tobon-Velasco","year":"2014","journal-title":"CNS Neurol. Disord. Drug Targets"},{"key":"B107","doi-asserted-by":"publisher","DOI":"10.1186\/1742-2094-2-24","article-title":"The microglial \u201cactivation\u201d continuum: From innate to adaptive responses.","volume":"2","author":"Town","year":"2005","journal-title":"J. Neuroinflammation"},{"key":"B108","doi-asserted-by":"publisher","first-page":"475","DOI":"10.1016\/j.neuroscience.2012.08.046","article-title":"Adolescent binge drinking increases expression of the danger signal receptor agonist HMGB1 and Toll-like receptors in the adult prefrontal cortex.","volume":"226","author":"Vetreno","year":"2012","journal-title":"Neuroscience"},{"key":"B109","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2015.00035","article-title":"Binge ethanol exposure during adolescence leads to a persistent loss of neurogenesis in the dorsal and ventral hippocampus that is associated with impaired adult cognitive functioning.","volume":"9","author":"Vetreno","year":"2015","journal-title":"Front. Neurosci."},{"key":"B110","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0204500","article-title":"Adolescent binge ethanol-induced loss of basal forebrain cholinergic neurons and neuroimmune activation are prevented by exercise and indomethacin.","volume":"13","author":"Vetreno","year":"2018","journal-title":"PLoS One"},{"key":"B111","doi-asserted-by":"publisher","DOI":"10.1111\/adb.12731","article-title":"Neuroimmune and epigenetic involvement in adolescent binge ethanol-induced loss of basal forebrain cholinergic neurons: Restoration with voluntary exercise.","volume":"25","author":"Vetreno","year":"2020","journal-title":"Addict. Biol."},{"key":"B112","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0113421","article-title":"Adolescent, but not adult, binge ethanol exposure leads to persistent global reductions of choline acetyltransferase expressing neurons in brain.","volume":"9","author":"Vetreno","year":"2014","journal-title":"PLoS One"},{"key":"B113","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2018.00200","article-title":"Persistent adult neuroimmune activation and loss of hippocampal neurogenesis following adolescent ethanol exposure: Blockade by exercise and the anti-inflammatory drug indomethacin.","volume":"12","author":"Vetreno","year":"2018","journal-title":"Front. Neurosci."},{"key":"B114","doi-asserted-by":"publisher","first-page":"333","DOI":"10.1016\/j.bbi.2016.09.018","article-title":"Adolescent intermittent ethanol reduces serotonin expression in the adult raphe nucleus and upregulates innate immune expression that is prevented by exercise.","volume":"60","author":"Vetreno","year":"2017","journal-title":"Brain Behav. Immun."},{"key":"B115","doi-asserted-by":"publisher","first-page":"52","DOI":"10.1016\/j.nbd.2013.07.002","article-title":"Increased receptor for advanced glycation end product expression in the human alcoholic prefrontal cortex is linked to adolescent drinking.","volume":"59","author":"Vetreno","year":"2013","journal-title":"Neurobiol. Dis."},{"key":"B116","doi-asserted-by":"publisher","first-page":"1747","DOI":"10.1111\/acer.14669","article-title":"Increased toll-like receptor-MyD88-NFkappaB-proinflammatory neuroimmune signaling in the orbitofrontal cortex of human alcohol use disorder.","volume":"45","author":"Vetreno","year":"2021","journal-title":"Alcohol Clin. Exp. Res."},{"key":"B117","doi-asserted-by":"crossref","first-page":"S527","DOI":"10.3233\/JAD-2010-100501","article-title":"Why women have more Alzheimer\u2019s disease than men: Gender and mitochondrial toxicity of amyloid-beta peptide","volume":"20","author":"Vina","year":"2010","journal-title":"J. Alzheimers Dis"},{"key":"B118","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1016\/0197-4580(90)90056-6","article-title":"Cell loss and shrinkage in the nucleus basalis Meynert complex in Alzheimer\u2019s disease.","volume":"11","author":"Vogels","year":"1990","journal-title":"Neurobiol. Aging"},{"key":"B119","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1055\/s-0030-1251503","article-title":"The role of HMGB1\/RAGE in inflammatory cardiomyopathy.","volume":"36","author":"Volz","year":"2010","journal-title":"Semin. Thrombosis Hemostasis"},{"key":"B120","doi-asserted-by":"crossref","first-page":"947","DOI":"10.1159\/000110455","article-title":"Role of the toll-like receptor 4 in neuroinflammation in Alzheimer\u2019s disease.","volume":"20","author":"Walter","year":"2007","journal-title":"Cell. Physiol. Biochem."},{"key":"B121","doi-asserted-by":"crossref","first-page":"2066","DOI":"10.1111\/acer.13511","article-title":"Alcohol and stress activation of microglia and neurons: Brain regional effects.","volume":"41","author":"Walter","year":"2017","journal-title":"Alcohol. Clin. Exp. Res."},{"key":"B122","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1016\/j.expneurol.2005.06.020","article-title":"Apoptotic signals within the basal forebrain cholinergic neurons in Alzheimer\u2019s disease.","volume":"195","author":"Wu","year":"2005","journal-title":"Exp. Neurol."},{"key":"B123","first-page":"4115","article-title":"The lesion analysis of cholinergic neurons in 5XFAD mouse model in the three-dimensional level of whole brain.","volume":"55","author":"Yan","year":"2018","journal-title":"Mol. Neurobiol."},{"key":"B124","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.00484","article-title":"Targeting inflammation driven by HMGB1.","volume":"11","author":"Yang","year":"2020","journal-title":"Front. Immunol."},{"key":"B125","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1016\/0006-8993(93)91714-4","article-title":"Differential development of cholinergic nerve terminal markers in rat brain regions: Implications for nerve terminal density, impulse activity and specific gene expression.","volume":"601","author":"Zahalka","year":"1993","journal-title":"Brain Res."},{"key":"B126","doi-asserted-by":"publisher","first-page":"1015","DOI":"10.1093\/brain\/awr032","article-title":"Activation of toll-like receptor, RAGE and HMGB1 signalling in malformations of cortical development.","volume":"134","author":"Zurolo","year":"2011","journal-title":"Brain"}],"container-title":["Frontiers in Aging Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnagi.2025.1531628\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,19]],"date-time":"2025-02-19T06:53:21Z","timestamp":1739948001000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnagi.2025.1531628\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,19]]},"references-count":126,"alternative-id":["10.3389\/fnagi.2025.1531628"],"URL":"https:\/\/doi.org\/10.3389\/fnagi.2025.1531628","relation":{},"ISSN":["1663-4365"],"issn-type":[{"value":"1663-4365","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,2,19]]},"article-number":"1531628"}}