{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T22:51:23Z","timestamp":1787698283293,"version":"build-2784847793"},"reference-count":75,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2026,1,7]],"date-time":"2026-01-07T00:00:00Z","timestamp":1767744000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH\/NIAAA","award":["AA-011431 (SMdlM)"],"award-info":[{"award-number":["AA-011431 (SMdlM)"]}]},{"name":"NIH\/NIAAA","award":["AA028408 (SMdlM)"],"award-info":[{"award-number":["AA028408 (SMdlM)"]}]},{"name":"NIH\/NIAAA","award":["AA032106 (SMdlM)"],"award-info":[{"award-number":["AA032106 (SMdlM)"]}]},{"name":"NIH\/NIAAA","award":["R28AA012725 (BTRC)"],"award-info":[{"award-number":["R28AA012725 (BTRC)"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Background: Alcohol use disorder (AUD) is associated with chronic heavy or repeated binge alcohol abuse, which can cause alcohol-related brain damage (ARBD) marked by neurobehavioral, cognitive, and motor deficits. The anterior frontal lobe and cerebellar vermis are two of the major targets of ARBD in humans with AUD and in experimental alcohol exposed models. Alcohol\u2019s neurotoxic and neurodegenerative effects include impairments in signaling through insulin and insulin-like growth factor (IGF) pathways that regulate energy metabolism. This human AUD study was inspired by a recent report suggesting that dysfunction of the frontal lobe incretin network in experimental ARBD is linked to known impairments in brain insulin\/IGF signaling. Objective: The overarching goal was to investigate whether AUD is associated with dysfunction of the brain\u2019s incretin network, focusing on the cerebellum and frontal lobe. Methods: Fresh frozen postmortem cerebellar vermis and anterior frontal lobe tissues from adult male AUD (n = 6) and control (n = 6) donors were processed for protein extraction. Duplex enzyme-linked immunosorbent assays (ELISAs) were used to assess immunoreactivity to neurofilament light chain (NfL) as a marker of neurodegeneration. A multiplex ELISA was used to measure immunoreactivity to a panel of gut hormones, including incretin polypeptides. Results: AUD was associated with significantly increased NfL immunoreactivity in both the cerebellar vermis and anterior frontal lobe. However, the patterns of AUD-related alterations in gut hormone immunoreactivity differed regionally. AUD reduced pancreatic polypeptide immunoreactivity in the cerebellar vermis, and GIP, GLP-1, leptin, and ghrelin in the frontal lobe. Conclusions: (1) Increased NfL may serve as a useful biomarker of neurodegeneration in AUD. (2) AUD\u2019s adverse effects on neuroendocrine signaling networks differ in the cerebellar vermis and anterior frontal region, although both are significant targets of ARBD. (3) The finding of AUD-associated reductions in frontal lobe GIP and GLP-1 suggests that therapeutic targeting with incretin receptor agonists may help restore energy metabolism and neurobehavioral and cognitive functions linked to their networks.<\/jats:p>","DOI":"10.3390\/biom16010099","type":"journal-article","created":{"date-parts":[[2026,1,7]],"date-time":"2026-01-07T09:34:12Z","timestamp":1767778452000},"page":"99","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Impaired Brain Incretin and Gut Hormone Expression in Human Alcohol-Related Brain Damage: Opportunities for Therapeutic Targeting"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5886-2306","authenticated-orcid":false,"given":"Suzanne M.","family":"de la Monte","sequence":"first","affiliation":[{"name":"Departments of Pathology and Laboratory Medicine, Neurology, Neurosurgery and Medicine, Rhode Island Hospital, Alpert Medical School of Brown University, Brown University Health, Providence, RI 02903, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming","family":"Tong","sequence":"additional","affiliation":[{"name":"Department of Medicine, Rhode Island Hospital, Alpert Medical School of Brown University, Brown University Health, Providence, RI 02903, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rolf I.","family":"Carlson","sequence":"additional","affiliation":[{"name":"Department of Medicine, Rhode Island Hospital, Alpert Medical School of Brown University, Brown University Health, Providence, RI 02903, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Greg","family":"Sutherland","sequence":"additional","affiliation":[{"name":"Charles Perkins Centre and School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW 2006, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"994","DOI":"10.1016\/j.neurobiolaging.2005.05.007","article-title":"Dysmorphology and microstructural degradation of the corpus callosum: Interaction of age and alcoholism","volume":"27","author":"Pfefferbaum","year":"2006","journal-title":"Neurobiol. 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