Ethanol consumption aggravates amyloid pathology and neuroinflammation in Alzheimer’s disease associated with inflammasome activation and ASC speck propagation
Abstract Background Alcohol use disorder (AUD) has been associated with Alzheimer’s disease (AD) and dementia, yet the underlying mechanisms and specific role of ethanol in AD progression remain poorly understood. Neuroinflammation has emerged as a key contributor to both AD pathogenesis and ethanol...
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BMC
2025-07-01
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| Series: | Journal of Neuroinflammation |
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| Online Access: | https://doi.org/10.1186/s12974-025-03501-8 |
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| author | Veronika Brezani Radhika S. Joshi Marti Ortega-Ribera Prashanth Thevkar Nagesh Viliam Brezani Adam Zivny Evelyn A. Kurt-Jones Douglas T. Golenbock Gyongyi Szabo |
| author_facet | Veronika Brezani Radhika S. Joshi Marti Ortega-Ribera Prashanth Thevkar Nagesh Viliam Brezani Adam Zivny Evelyn A. Kurt-Jones Douglas T. Golenbock Gyongyi Szabo |
| author_sort | Veronika Brezani |
| collection | DOAJ |
| description | Abstract Background Alcohol use disorder (AUD) has been associated with Alzheimer’s disease (AD) and dementia, yet the underlying mechanisms and specific role of ethanol in AD progression remain poorly understood. Neuroinflammation has emerged as a key contributor to both AD pathogenesis and ethanol-induced brain damage. Activation of innate immune cells and signaling pathways, in particular NLRP3 inflammasome, plays a pivotal role in both AD and ethanol-induced inflammation. Thus, we postulated that excessive ethanol consumption could contribute to AD progression via amplified neuroinflammation. Methods The 12–15-month-old WT and APP/PS1 mice received water or ethanol (3.5 g/kg) binge every alternate day for a period of one month. The effects of ethanol on amyloid pathology, microglia and astrocyte activation, and NLRP3 inflammasome activation were evaluated in the mouse brains. The effect of ethanol and amyloid β on NLRP3 inflammasome signaling was further studied in primary glial cells. Results In this study, we show that repeated ethanol binges aggravate the amyloid pathology and plaque burden in the hippocampus of APP/PS1 mice. Furthermore, we demonstrate the additive effect of ethanol administration on NLRP3 inflammasome activation, IL-1β release, and ASC aggregation in the brains of APP/PS1 mice and primary glia cultures. Our study also reveals a strong astrocyte activation by ethanol in the hippocampus of APP/PS1 mice as demonstrated by significantly increased GFAP and ALDH1L1 protein levels. Further in vitro analysis revealed that ethanol potentiates the effect of amyloid β to increase the NLRP3 inflammasome activation in both primary astrocytes and microglia. Lastly, we demonstrate that glia-produced ASC specks induce IL-1β in microglia and astrocytes and induce ROS in SH-SY5Y neurons, contributing to sustained neuroinflammation in AD. Conclusion Collectively, our results demonstrate that ethanol consumption exacerbates features of AD pathology associated with amplified neuroinflammation and NLRP3/ASC inflammasome activation, which may play an important role in the disease progression and severity. |
| format | Article |
| id | doaj-art-4dd304a4a45044caa203e4d19f7f76b4 |
| institution | DOAJ |
| issn | 1742-2094 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | BMC |
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| series | Journal of Neuroinflammation |
| spelling | doaj-art-4dd304a4a45044caa203e4d19f7f76b42025-08-20T03:05:16ZengBMCJournal of Neuroinflammation1742-20942025-07-0122112210.1186/s12974-025-03501-8Ethanol consumption aggravates amyloid pathology and neuroinflammation in Alzheimer’s disease associated with inflammasome activation and ASC speck propagationVeronika Brezani0Radhika S. Joshi1Marti Ortega-Ribera2Prashanth Thevkar Nagesh3Viliam Brezani4Adam Zivny5Evelyn A. Kurt-Jones6Douglas T. Golenbock7Gyongyi Szabo8Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical SchoolDepartment of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical SchoolDepartment of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical SchoolDepartment of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical SchoolDepartment of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical SchoolDepartment of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical SchoolDepartment of Medicine, University of Massachusetts Chan Medical SchoolDepartment of Medicine, University of Massachusetts Chan Medical SchoolDepartment of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical SchoolAbstract Background Alcohol use disorder (AUD) has been associated with Alzheimer’s disease (AD) and dementia, yet the underlying mechanisms and specific role of ethanol in AD progression remain poorly understood. Neuroinflammation has emerged as a key contributor to both AD pathogenesis and ethanol-induced brain damage. Activation of innate immune cells and signaling pathways, in particular NLRP3 inflammasome, plays a pivotal role in both AD and ethanol-induced inflammation. Thus, we postulated that excessive ethanol consumption could contribute to AD progression via amplified neuroinflammation. Methods The 12–15-month-old WT and APP/PS1 mice received water or ethanol (3.5 g/kg) binge every alternate day for a period of one month. The effects of ethanol on amyloid pathology, microglia and astrocyte activation, and NLRP3 inflammasome activation were evaluated in the mouse brains. The effect of ethanol and amyloid β on NLRP3 inflammasome signaling was further studied in primary glial cells. Results In this study, we show that repeated ethanol binges aggravate the amyloid pathology and plaque burden in the hippocampus of APP/PS1 mice. Furthermore, we demonstrate the additive effect of ethanol administration on NLRP3 inflammasome activation, IL-1β release, and ASC aggregation in the brains of APP/PS1 mice and primary glia cultures. Our study also reveals a strong astrocyte activation by ethanol in the hippocampus of APP/PS1 mice as demonstrated by significantly increased GFAP and ALDH1L1 protein levels. Further in vitro analysis revealed that ethanol potentiates the effect of amyloid β to increase the NLRP3 inflammasome activation in both primary astrocytes and microglia. Lastly, we demonstrate that glia-produced ASC specks induce IL-1β in microglia and astrocytes and induce ROS in SH-SY5Y neurons, contributing to sustained neuroinflammation in AD. Conclusion Collectively, our results demonstrate that ethanol consumption exacerbates features of AD pathology associated with amplified neuroinflammation and NLRP3/ASC inflammasome activation, which may play an important role in the disease progression and severity.https://doi.org/10.1186/s12974-025-03501-8Alzheimer’sAlcohol use disorderEthanolNeuroinflammationInflammasomeASC specks |
| spellingShingle | Veronika Brezani Radhika S. Joshi Marti Ortega-Ribera Prashanth Thevkar Nagesh Viliam Brezani Adam Zivny Evelyn A. Kurt-Jones Douglas T. Golenbock Gyongyi Szabo Ethanol consumption aggravates amyloid pathology and neuroinflammation in Alzheimer’s disease associated with inflammasome activation and ASC speck propagation Journal of Neuroinflammation Alzheimer’s Alcohol use disorder Ethanol Neuroinflammation Inflammasome ASC specks |
| title | Ethanol consumption aggravates amyloid pathology and neuroinflammation in Alzheimer’s disease associated with inflammasome activation and ASC speck propagation |
| title_full | Ethanol consumption aggravates amyloid pathology and neuroinflammation in Alzheimer’s disease associated with inflammasome activation and ASC speck propagation |
| title_fullStr | Ethanol consumption aggravates amyloid pathology and neuroinflammation in Alzheimer’s disease associated with inflammasome activation and ASC speck propagation |
| title_full_unstemmed | Ethanol consumption aggravates amyloid pathology and neuroinflammation in Alzheimer’s disease associated with inflammasome activation and ASC speck propagation |
| title_short | Ethanol consumption aggravates amyloid pathology and neuroinflammation in Alzheimer’s disease associated with inflammasome activation and ASC speck propagation |
| title_sort | ethanol consumption aggravates amyloid pathology and neuroinflammation in alzheimer s disease associated with inflammasome activation and asc speck propagation |
| topic | Alzheimer’s Alcohol use disorder Ethanol Neuroinflammation Inflammasome ASC specks |
| url | https://doi.org/10.1186/s12974-025-03501-8 |
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