Integrin β3-Mediated Cell Senescence Associates with Gut Inflammation and Intestinal Degeneration in Models of Alzheimer's Disease.
Integrin β3-Mediated Cell Senescence Associates with Gut Inflammation and Intestinal Degeneration in Models of Alzheimer's Disease.
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DOI：
10.3390/ijms24065697
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发表时间：
2023-03-16
影响因子：
5.6
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阿尔茨海默病（AD）是一种神经退行性疾病，其特征是记忆丧失和性格改变，最终导致痴呆。目前，全球有 5000 万人患有与 AD 相关的痴呆症，而 AD 病理和认知能力下降的发病机制尚不清楚。虽然 AD 主要是一种大脑神经系统疾病，但 AD 患者经常会出现肠道疾病，并且肠道异常被认为是 AD 和相关痴呆症发展的主要危险因素。然而，AD 中介导肠道损伤以及导致肠道异常和脑损伤之间恶性循环的机制仍然未知。在本研究中，对不同年龄的AD小鼠结肠组织的蛋白质组学数据进行了生物信息学分析。我们发现，在患有 AD 的小鼠结肠组织中，整合素 β3 和 β-半乳糖苷酶 (β-gal) 这两种细胞衰老标志物的水平随着年龄的增长而增加。基于先进人工智能 (AI) 的 AD 风险预测也证明了整合素 β3 和 β-gal 与 AD 表型之间的关联。此外，我们发现 AD 小鼠结肠组织中整合素 β3 水平升高伴随着衰老表型和免疫细胞积累。此外，整合素β3基因下调消除了与AD相关的结肠上皮细胞中上调的衰老标志物和炎症反应。我们对 AD 期间炎症反应的分子作用有了新的认识，并表明整合素 β3 可能作为介导这种疾病肠道异常的新靶点。
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.