Liver-specific expression of ANGPTL8 promotes Alzheimer’s disease progression through activating microglial pyroptosis
Abstract Introduction Liver dysfunction contributes to Alzheimer’s disease (AD) pathogenesis, and evidence suggests that the liver is involved in amyloid β (Aβ) clearance, and regulates Aβ deposition in the brain. However, the specific regulatory mechanism remains elusive. Objectives Angiopoietin-li...
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2025-07-01
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| Online Access: | https://doi.org/10.1186/s12974-025-03487-3 |
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| author | Jiarui Wei Lin Hu Shufan Xu Fan Yang Fusheng Liao Ying Tang Xin Shen Xiaoqiao Zhang Xinggang Fang Yifan Li Li Ding Zhuo Chen Shanchun Su Junhua Cheng Yong Huang Qian Chen Daqing Ma Qiufang Zhang Xingrong Guo |
| author_facet | Jiarui Wei Lin Hu Shufan Xu Fan Yang Fusheng Liao Ying Tang Xin Shen Xiaoqiao Zhang Xinggang Fang Yifan Li Li Ding Zhuo Chen Shanchun Su Junhua Cheng Yong Huang Qian Chen Daqing Ma Qiufang Zhang Xingrong Guo |
| author_sort | Jiarui Wei |
| collection | DOAJ |
| description | Abstract Introduction Liver dysfunction contributes to Alzheimer’s disease (AD) pathogenesis, and evidence suggests that the liver is involved in amyloid β (Aβ) clearance, and regulates Aβ deposition in the brain. However, the specific regulatory mechanism remains elusive. Objectives Angiopoietin-like protein 8 (ANGPTL8), a high expression of liver-specific secreted proinflammatory factor, crosses the blood‒brain barrier from the bloodstream to abnormally activate microglia and promote AD progression. Methods The ANGPTL8−/− mice and 5 × FAD mice were crossed mutated and subjected to the Morris water maze test and novel object recognition test to assess cognitive ability in different cohorts. Thioflavin-S, NeuN, and Nissl staining were used to assess Aβ deposition and neuron loss. The number of phagocytic microglia was evaluated with Fitc latex beads. Adeno-associated virus 8 (AAV8) hydrodynamically injected restored the liver ANGPTL8 levels of ANGPTL8−/− 5 × FAD mice for further experiments. Single-cell RNA sequencing, bulk RNA sequencing and transmission electron microscopy were used to explore the role of ANGPTL8 in regulating AD progression, and drug screening was carried out to identify an effective inhibitor of ANGPTL8. Results ANGPTL8 knockout improved cognitive function and reduced Aβ deposition by reducing microgliosis and microglial activation in 5xFAD mice. Mechanistically, ANGPTL8 crossed the blood‒brain barrier and interacted with the microglial membrane receptor PirB/LILRB2. This interaction subsequently activated the downstream NLRP3 inflammasome, leading to microglial pyroptosis and exacerbating the Aβ-induced release of inflammatory factors, thereby accelerating AD progression. Furthermore, the administration of metformin, an ANGPTL8 inhibitor, improved learning and memory deficits in 5 × FAD mice by negating microglial pyroptosis and neuroinflammation. Conclusions ANGPTL8 aggravates microglial pyroptosis via the PirB/NLRP3 pathway to accelerate the pathogenesis of AD. Targeting high expression of ANGPTL8 in the liver may hold potential for developing therapies for AD. |
| format | Article |
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| institution | Kabale University |
| issn | 1742-2094 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | BMC |
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| series | Journal of Neuroinflammation |
| spelling | doaj-art-24ffcfcbd2d14a9283d529e63840ebfa2025-08-20T04:03:02ZengBMCJournal of Neuroinflammation1742-20942025-07-0122112310.1186/s12974-025-03487-3Liver-specific expression of ANGPTL8 promotes Alzheimer’s disease progression through activating microglial pyroptosisJiarui Wei0Lin Hu1Shufan Xu2Fan Yang3Fusheng Liao4Ying Tang5Xin Shen6Xiaoqiao Zhang7Xinggang Fang8Yifan Li9Li Ding10Zhuo Chen11Shanchun Su12Junhua Cheng13Yong Huang14Qian Chen15Daqing Ma16Qiufang Zhang17Xingrong Guo18Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei Provincial Clinical Research Center for Umbilical Cord Blood Hematopoietic Stem Cells, Department of pharmacology of School of Basic Medical Sciences, Department of Geriatrics & General Medicine of Taihe Hospital, Hubei University of MedicineHubei Key Laboratory of Embryonic Stem Cell Research, Hubei Provincial Clinical Research Center for Umbilical Cord Blood Hematopoietic Stem Cells, Department of pharmacology of School of Basic Medical Sciences, Department of Geriatrics & General Medicine of Taihe Hospital, Hubei University of MedicineHubei Key Laboratory of Embryonic Stem Cell Research, Hubei Provincial Clinical Research Center for Umbilical Cord Blood Hematopoietic Stem Cells, Department of pharmacology of School of Basic Medical Sciences, Department of Geriatrics & General Medicine of Taihe Hospital, Hubei University of MedicineHubei Key Laboratory of Embryonic Stem Cell Research, Hubei Provincial Clinical Research Center for Umbilical Cord Blood Hematopoietic Stem Cells, Department of pharmacology of School of Basic Medical Sciences, Department of Geriatrics & General Medicine of Taihe Hospital, Hubei University of MedicineHubei Key Laboratory of Embryonic Stem Cell Research, Hubei Provincial Clinical Research Center for Umbilical Cord Blood Hematopoietic Stem Cells, Department of pharmacology of School of Basic Medical Sciences, Department of Geriatrics & General Medicine of Taihe Hospital, Hubei University of MedicineHubei Key Laboratory of Embryonic Stem Cell Research, Hubei Provincial Clinical Research Center for Umbilical Cord Blood Hematopoietic Stem Cells, Department of pharmacology of School of Basic Medical Sciences, Department of Geriatrics & General Medicine of Taihe Hospital, Hubei University of MedicineHubei Key Laboratory of Embryonic Stem Cell Research, Hubei Provincial Clinical Research Center for Umbilical Cord Blood Hematopoietic Stem Cells, Department of pharmacology of School of Basic Medical Sciences, Department of Geriatrics & General Medicine of Taihe Hospital, Hubei University of MedicineHubei Key Laboratory of Embryonic Stem Cell Research, Hubei Provincial Clinical Research Center for Umbilical Cord Blood Hematopoietic Stem Cells, Department of pharmacology of School of Basic Medical Sciences, Department of Geriatrics & General Medicine of Taihe Hospital, Hubei University of MedicineHubei Key Laboratory of Embryonic Stem Cell Research, Hubei Provincial Clinical Research Center for Umbilical Cord Blood Hematopoietic Stem Cells, Department of pharmacology of School of Basic Medical Sciences, Department of Geriatrics & General Medicine of Taihe Hospital, Hubei University of MedicineHubei Key Laboratory of Embryonic Stem Cell Research, Hubei Provincial Clinical Research Center for Umbilical Cord Blood Hematopoietic Stem Cells, Department of pharmacology of School of Basic Medical Sciences, Department of Geriatrics & General Medicine of Taihe Hospital, Hubei University of MedicineHubei Key Laboratory of Embryonic Stem Cell Research, Hubei Provincial Clinical Research Center for Umbilical Cord Blood Hematopoietic Stem Cells, Department of pharmacology of School of Basic Medical Sciences, Department of Geriatrics & General Medicine of Taihe Hospital, Hubei University of MedicineHubei Key Laboratory of Embryonic Stem Cell Research, Hubei Provincial Clinical Research Center for Umbilical Cord Blood Hematopoietic Stem Cells, Department of pharmacology of School of Basic Medical Sciences, Department of Geriatrics & General Medicine of Taihe Hospital, Hubei University of MedicineHubei Key Laboratory of Embryonic Stem Cell Research, Hubei Provincial Clinical Research Center for Umbilical Cord Blood Hematopoietic Stem Cells, Department of pharmacology of School of Basic Medical Sciences, Department of Geriatrics & General Medicine of Taihe Hospital, Hubei University of MedicineHubei Key Laboratory of Embryonic Stem Cell Research, Hubei Provincial Clinical Research Center for Umbilical Cord Blood Hematopoietic Stem Cells, Department of pharmacology of School of Basic Medical Sciences, Department of Geriatrics & General Medicine of Taihe Hospital, Hubei University of MedicineHubei Key Laboratory of Embryonic Stem Cell Research, Hubei Provincial Clinical Research Center for Umbilical Cord Blood Hematopoietic Stem Cells, Department of pharmacology of School of Basic Medical Sciences, Department of Geriatrics & General Medicine of Taihe Hospital, Hubei University of MedicinePerioperative and Systems Medicine Laboratory and Department of Anaesthesia, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child HealthPerioperative and Systems Medicine Laboratory and Department of Anaesthesia, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child HealthHubei Key Laboratory of Embryonic Stem Cell Research, Hubei Provincial Clinical Research Center for Umbilical Cord Blood Hematopoietic Stem Cells, Department of pharmacology of School of Basic Medical Sciences, Department of Geriatrics & General Medicine of Taihe Hospital, Hubei University of MedicineHubei Key Laboratory of Embryonic Stem Cell Research, Hubei Provincial Clinical Research Center for Umbilical Cord Blood Hematopoietic Stem Cells, Department of pharmacology of School of Basic Medical Sciences, Department of Geriatrics & General Medicine of Taihe Hospital, Hubei University of MedicineAbstract Introduction Liver dysfunction contributes to Alzheimer’s disease (AD) pathogenesis, and evidence suggests that the liver is involved in amyloid β (Aβ) clearance, and regulates Aβ deposition in the brain. However, the specific regulatory mechanism remains elusive. Objectives Angiopoietin-like protein 8 (ANGPTL8), a high expression of liver-specific secreted proinflammatory factor, crosses the blood‒brain barrier from the bloodstream to abnormally activate microglia and promote AD progression. Methods The ANGPTL8−/− mice and 5 × FAD mice were crossed mutated and subjected to the Morris water maze test and novel object recognition test to assess cognitive ability in different cohorts. Thioflavin-S, NeuN, and Nissl staining were used to assess Aβ deposition and neuron loss. The number of phagocytic microglia was evaluated with Fitc latex beads. Adeno-associated virus 8 (AAV8) hydrodynamically injected restored the liver ANGPTL8 levels of ANGPTL8−/− 5 × FAD mice for further experiments. Single-cell RNA sequencing, bulk RNA sequencing and transmission electron microscopy were used to explore the role of ANGPTL8 in regulating AD progression, and drug screening was carried out to identify an effective inhibitor of ANGPTL8. Results ANGPTL8 knockout improved cognitive function and reduced Aβ deposition by reducing microgliosis and microglial activation in 5xFAD mice. Mechanistically, ANGPTL8 crossed the blood‒brain barrier and interacted with the microglial membrane receptor PirB/LILRB2. This interaction subsequently activated the downstream NLRP3 inflammasome, leading to microglial pyroptosis and exacerbating the Aβ-induced release of inflammatory factors, thereby accelerating AD progression. Furthermore, the administration of metformin, an ANGPTL8 inhibitor, improved learning and memory deficits in 5 × FAD mice by negating microglial pyroptosis and neuroinflammation. Conclusions ANGPTL8 aggravates microglial pyroptosis via the PirB/NLRP3 pathway to accelerate the pathogenesis of AD. Targeting high expression of ANGPTL8 in the liver may hold potential for developing therapies for AD.https://doi.org/10.1186/s12974-025-03487-3ANGPTL8NeuroinflammationLiver‒brain axisMicroglial pyroptosisAlzheimer's disease |
| spellingShingle | Jiarui Wei Lin Hu Shufan Xu Fan Yang Fusheng Liao Ying Tang Xin Shen Xiaoqiao Zhang Xinggang Fang Yifan Li Li Ding Zhuo Chen Shanchun Su Junhua Cheng Yong Huang Qian Chen Daqing Ma Qiufang Zhang Xingrong Guo Liver-specific expression of ANGPTL8 promotes Alzheimer’s disease progression through activating microglial pyroptosis Journal of Neuroinflammation ANGPTL8 Neuroinflammation Liver‒brain axis Microglial pyroptosis Alzheimer's disease |
| title | Liver-specific expression of ANGPTL8 promotes Alzheimer’s disease progression through activating microglial pyroptosis |
| title_full | Liver-specific expression of ANGPTL8 promotes Alzheimer’s disease progression through activating microglial pyroptosis |
| title_fullStr | Liver-specific expression of ANGPTL8 promotes Alzheimer’s disease progression through activating microglial pyroptosis |
| title_full_unstemmed | Liver-specific expression of ANGPTL8 promotes Alzheimer’s disease progression through activating microglial pyroptosis |
| title_short | Liver-specific expression of ANGPTL8 promotes Alzheimer’s disease progression through activating microglial pyroptosis |
| title_sort | liver specific expression of angptl8 promotes alzheimer s disease progression through activating microglial pyroptosis |
| topic | ANGPTL8 Neuroinflammation Liver‒brain axis Microglial pyroptosis Alzheimer's disease |
| url | https://doi.org/10.1186/s12974-025-03487-3 |
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