Adolescent binge alcohol exposure accelerates Alzheimer’s disease-associated basal forebrain neuropathology through proinflammatory HMGB1 signaling
Human studies suggest that heavy alcohol use may be an etiological factor contributing to the development of Alzheimer’s disease (AD) neuropathology. Both alcohol use disorder (AUD) and AD share common underlying neuropathology, including proinflammatory high-mobility group box 1 (HMGB1)-mediated ne...
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Frontiers Media S.A.
2025-02-01
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| Series: | Frontiers in Aging Neuroscience |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fnagi.2025.1531628/full |
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| author | Rachael P. Fisher Lindsay Matheny Sarrah Ankeny Liya Qin Leon G. Coleman Leon G. Coleman Ryan P. Vetreno Ryan P. Vetreno Ryan P. Vetreno |
| author_facet | Rachael P. Fisher Lindsay Matheny Sarrah Ankeny Liya Qin Leon G. Coleman Leon G. Coleman Ryan P. Vetreno Ryan P. Vetreno Ryan P. Vetreno |
| author_sort | Rachael P. Fisher |
| collection | DOAJ |
| description | Human studies suggest that heavy alcohol use may be an etiological factor contributing to the development of Alzheimer’s 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 – 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 Hmgb1 and the HMGB1 receptors Rage and Tlr4 as well as microglial activation and increased intraneuronal Aβ1–42 accumulation in association with reduced cholinergic neuron marker expression (ChAT). In the 5xFAD mouse model (Experiment 2), AIE accelerated AD-associated induction of Hmgb1 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. |
| format | Article |
| id | doaj-art-b3c0598af61c49bd95fc344abb2fcef2 |
| institution | DOAJ |
| issn | 1663-4365 |
| language | English |
| publishDate | 2025-02-01 |
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| spelling | doaj-art-b3c0598af61c49bd95fc344abb2fcef22025-08-20T02:43:49ZengFrontiers Media S.A.Frontiers in Aging Neuroscience1663-43652025-02-011710.3389/fnagi.2025.15316281531628Adolescent binge alcohol exposure accelerates Alzheimer’s disease-associated basal forebrain neuropathology through proinflammatory HMGB1 signalingRachael P. Fisher0Lindsay Matheny1Sarrah Ankeny2Liya Qin3Leon G. Coleman4Leon G. Coleman5Ryan P. Vetreno6Ryan P. Vetreno7Ryan P. Vetreno8Bowles Center for Alcohol Studies, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, United StatesBowles Center for Alcohol Studies, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, United StatesBowles Center for Alcohol Studies, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, United StatesBowles Center for Alcohol Studies, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, United StatesBowles Center for Alcohol Studies, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, United StatesDepartment of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, United StatesBowles Center for Alcohol Studies, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, United StatesDepartment of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, United StatesDepartment of Psychiatry, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, United StatesHuman studies suggest that heavy alcohol use may be an etiological factor contributing to the development of Alzheimer’s 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 – 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 Hmgb1 and the HMGB1 receptors Rage and Tlr4 as well as microglial activation and increased intraneuronal Aβ1–42 accumulation in association with reduced cholinergic neuron marker expression (ChAT). In the 5xFAD mouse model (Experiment 2), AIE accelerated AD-associated induction of Hmgb1 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.https://www.frontiersin.org/articles/10.3389/fnagi.2025.1531628/fullethanolneuroinflammationmicrogliacholinergic neuronsHMGB1 |
| spellingShingle | Rachael P. Fisher Lindsay Matheny Sarrah Ankeny Liya Qin Leon G. Coleman Leon G. Coleman Ryan P. Vetreno Ryan P. Vetreno Ryan P. Vetreno Adolescent binge alcohol exposure accelerates Alzheimer’s disease-associated basal forebrain neuropathology through proinflammatory HMGB1 signaling Frontiers in Aging Neuroscience ethanol neuroinflammation microglia cholinergic neurons HMGB1 |
| title | Adolescent binge alcohol exposure accelerates Alzheimer’s disease-associated basal forebrain neuropathology through proinflammatory HMGB1 signaling |
| title_full | Adolescent binge alcohol exposure accelerates Alzheimer’s disease-associated basal forebrain neuropathology through proinflammatory HMGB1 signaling |
| title_fullStr | Adolescent binge alcohol exposure accelerates Alzheimer’s disease-associated basal forebrain neuropathology through proinflammatory HMGB1 signaling |
| title_full_unstemmed | Adolescent binge alcohol exposure accelerates Alzheimer’s disease-associated basal forebrain neuropathology through proinflammatory HMGB1 signaling |
| title_short | Adolescent binge alcohol exposure accelerates Alzheimer’s disease-associated basal forebrain neuropathology through proinflammatory HMGB1 signaling |
| title_sort | adolescent binge alcohol exposure accelerates alzheimer s disease associated basal forebrain neuropathology through proinflammatory hmgb1 signaling |
| topic | ethanol neuroinflammation microglia cholinergic neurons HMGB1 |
| url | https://www.frontiersin.org/articles/10.3389/fnagi.2025.1531628/full |
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