Integrin β3-Mediated Cell Senescence Associates with Gut Inflammation and Intestinal Degeneration in Models of Alzheimer’s Disease
Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by memory loss and personality changes that ultimately lead to dementia. Currently, 50 million people worldwide suffer from dementia related to AD, and the pathogenesis underlying AD pathology and cognitive decline is unknown. Wh...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2023-03-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/24/6/5697 |
| _version_ | 1797611272057913344 |
|---|---|
| author | Xin Tun Evan J. Wang Zhenxiang Gao Kathleen Lundberg Rong Xu Di Hu |
| author_facet | Xin Tun Evan J. Wang Zhenxiang Gao Kathleen Lundberg Rong Xu Di Hu |
| author_sort | Xin Tun |
| collection | DOAJ |
| description | Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by memory loss and personality changes that ultimately lead to dementia. Currently, 50 million people worldwide suffer from dementia related to AD, and the pathogenesis underlying AD pathology and cognitive decline is unknown. While AD is primarily a neurological disease of the brain, individuals with AD often experience intestinal disorders, and gut abnormalities have been implicated as a major risk factor in the development of AD and relevant dementia. However, the mechanisms that mediate gut injury and contribute to the vicious cycle between gut abnormalities and brain injury in AD remain unknown. In the present study, a bioinformatics analysis was performed on the proteomics data of variously aged AD mouse colon tissues. We found that levels of integrin β3 and β-galactosidase (β-gal), two markers of cellular senescence, increased with age in the colonic tissue of mice with AD. The advanced artificial intelligence (AI)-based prediction of AD risk also demonstrated the association between integrin β3 and β-gal and AD phenotypes. Moreover, we showed that elevated integrin β3 levels were accompanied by senescence phenotypes and immune cell accumulation in AD mouse colonic tissue. Further, integrin β3 genetic downregulation abolished upregulated senescence markers and inflammatory responses in colonic epithelial cells in conditions associated with AD. We provide a new understanding of the molecular actions underpinning inflammatory responses during AD and suggest integrin β3 may function as novel target mediating gut abnormalities in this disease. |
| first_indexed | 2024-03-11T06:25:29Z |
| format | Article |
| id | doaj.art-da61177e253f4b8aa697e9ba7200491d |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T06:25:29Z |
| publishDate | 2023-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-da61177e253f4b8aa697e9ba7200491d2023-11-17T11:37:44ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-03-01246569710.3390/ijms24065697Integrin β3-Mediated Cell Senescence Associates with Gut Inflammation and Intestinal Degeneration in Models of Alzheimer’s DiseaseXin Tun0Evan J. Wang1Zhenxiang Gao2Kathleen Lundberg3Rong Xu4Di Hu5Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USACenter for Artificial Intelligence in Drug Discovery, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USACenter for Artificial Intelligence in Drug Discovery, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USAProteomics Center, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USACenter for Artificial Intelligence in Drug Discovery, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USADepartment of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USAAlzheimer’s disease (AD) is a neurodegenerative disorder characterized by memory loss and personality changes that ultimately lead to dementia. Currently, 50 million people worldwide suffer from dementia related to AD, and the pathogenesis underlying AD pathology and cognitive decline is unknown. While AD is primarily a neurological disease of the brain, individuals with AD often experience intestinal disorders, and gut abnormalities have been implicated as a major risk factor in the development of AD and relevant dementia. However, the mechanisms that mediate gut injury and contribute to the vicious cycle between gut abnormalities and brain injury in AD remain unknown. In the present study, a bioinformatics analysis was performed on the proteomics data of variously aged AD mouse colon tissues. We found that levels of integrin β3 and β-galactosidase (β-gal), two markers of cellular senescence, increased with age in the colonic tissue of mice with AD. The advanced artificial intelligence (AI)-based prediction of AD risk also demonstrated the association between integrin β3 and β-gal and AD phenotypes. Moreover, we showed that elevated integrin β3 levels were accompanied by senescence phenotypes and immune cell accumulation in AD mouse colonic tissue. Further, integrin β3 genetic downregulation abolished upregulated senescence markers and inflammatory responses in colonic epithelial cells in conditions associated with AD. We provide a new understanding of the molecular actions underpinning inflammatory responses during AD and suggest integrin β3 may function as novel target mediating gut abnormalities in this disease.https://www.mdpi.com/1422-0067/24/6/5697Alzheimer’s diseasecolonepithelial senescenceinflammationintegrin β3 |
| spellingShingle | Xin Tun Evan J. Wang Zhenxiang Gao Kathleen Lundberg Rong Xu Di Hu Integrin β3-Mediated Cell Senescence Associates with Gut Inflammation and Intestinal Degeneration in Models of Alzheimer’s Disease International Journal of Molecular Sciences Alzheimer’s disease colon epithelial senescence inflammation integrin β3 |
| title | Integrin β3-Mediated Cell Senescence Associates with Gut Inflammation and Intestinal Degeneration in Models of Alzheimer’s Disease |
| title_full | Integrin β3-Mediated Cell Senescence Associates with Gut Inflammation and Intestinal Degeneration in Models of Alzheimer’s Disease |
| title_fullStr | Integrin β3-Mediated Cell Senescence Associates with Gut Inflammation and Intestinal Degeneration in Models of Alzheimer’s Disease |
| title_full_unstemmed | Integrin β3-Mediated Cell Senescence Associates with Gut Inflammation and Intestinal Degeneration in Models of Alzheimer’s Disease |
| title_short | Integrin β3-Mediated Cell Senescence Associates with Gut Inflammation and Intestinal Degeneration in Models of Alzheimer’s Disease |
| title_sort | integrin β3 mediated cell senescence associates with gut inflammation and intestinal degeneration in models of alzheimer s disease |
| topic | Alzheimer’s disease colon epithelial senescence inflammation integrin β3 |
| url | https://www.mdpi.com/1422-0067/24/6/5697 |
| work_keys_str_mv | AT xintun integrinb3mediatedcellsenescenceassociateswithgutinflammationandintestinaldegenerationinmodelsofalzheimersdisease AT evanjwang integrinb3mediatedcellsenescenceassociateswithgutinflammationandintestinaldegenerationinmodelsofalzheimersdisease AT zhenxianggao integrinb3mediatedcellsenescenceassociateswithgutinflammationandintestinaldegenerationinmodelsofalzheimersdisease AT kathleenlundberg integrinb3mediatedcellsenescenceassociateswithgutinflammationandintestinaldegenerationinmodelsofalzheimersdisease AT rongxu integrinb3mediatedcellsenescenceassociateswithgutinflammationandintestinaldegenerationinmodelsofalzheimersdisease AT dihu integrinb3mediatedcellsenescenceassociateswithgutinflammationandintestinaldegenerationinmodelsofalzheimersdisease |