Unravelling neuronal death mechanisms: The role of cytokines and chemokines in immune imbalance in Alzheimer’s disease progression

IF 12.4 1区 医学 Q1 CELL BIOLOGY
Sneha Kumari , Rishika Dhapola , Prajjwal Sharma , Mohit Paidlewar , Balachandar Vellingiri , Bikash Medhi , Dibbanti HariKrishnaReddy
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引用次数: 0

Abstract

Alzheimer's disease (AD) is marked by neuroinflammation, neurodegeneration and cognitive decline, with emerging evidence highlighting the critical roles of cytokines and chemokines in its pathogenesis. Regulated cell death is a highly structured and meticulously coordinated series of molecular and signalling processes involving gene expression and protein activity. This mechanism is essential for normal developmental processes and the preservation of tissue homeostasis. Abnormal regulation of inflammatory mediators contributes to or results from amyloid-β and tangle deposition, triggers oxidative stress, excitotoxicity, and neuroinflammation, leads to cell death through multiple mechanisms, including apoptosis, ferroptosis, pyroptosis, PANoptosis, etc. The pathogenetic mechanisms responsible for neuronal death and dysfunction in AD are not yet fully understood. This review seeks to compile evidence for the various modes of neuronal cell death in AD and to explore how the neuroinflammatory environment of the AD brain influences these distinct forms of cell death. Several inflammatory signalling cascades are involved in above discussed neuronal death mechanisms, such as RAGE/NF-κB, NLRP3 inflammasome, AMPK/mTOR/ULK1, cGAS-STING, RIPK1/RIPK3/MLKL, GPX4/Nrf2 and JAK-STAT pathways. Therapeutic drugs such as Magnolol, Necrostatin-1, Salidroside, Azeliragon, DNL788, Baricitinib, Sargramostim, etc. targeting neuroinflammation-associated signaling pathways, have shown efficacy in preclinical and clinical studies mitigating AD pathology. Enhancing our comprehension of neuronal death mechanisms could elucidate disease pathogenesis, offer insights for therapeutic approaches, and aid in developing modified animal models of AD.
揭示神经元死亡机制:细胞因子和趋化因子在阿尔茨海默病进展中免疫失衡的作用
阿尔茨海默病(AD)以神经炎症、神经变性和认知能力下降为特征,新出现的证据强调了细胞因子和趋化因子在其发病机制中的关键作用。调控细胞死亡是一个高度结构化和精心协调的一系列分子和信号过程,涉及基因表达和蛋白质活性。这一机制对正常发育过程和组织稳态的维持至关重要。炎症介质的异常调节导致淀粉样蛋白-β和缠结沉积,引发氧化应激、兴奋性毒性和神经炎症,并通过多种机制导致细胞死亡,包括凋亡、铁下垂、焦下垂、PANoptosis等。阿尔茨海默病神经元死亡和功能障碍的发病机制尚不完全清楚。本综述旨在收集阿尔茨海默病中各种神经元细胞死亡模式的证据,并探讨阿尔茨海默病大脑的神经炎症环境如何影响这些不同形式的细胞死亡。以上所讨论的神经元死亡机制涉及多种炎症信号级联通路,如RAGE/NF-κB、NLRP3炎性体、AMPK/mTOR/ULK1、cGAS-STING、RIPK1/RIPK3/MLKL、GPX4/Nrf2和JAK-STAT通路。厚朴酚、坏死性他汀-1、红柳苷、阿泽拉西根、DNL788、Baricitinib、Sargramostim等靶向神经炎症相关信号通路的治疗药物在临床前和临床研究中均显示出减轻AD病理的疗效。加强我们对神经元死亡机制的理解可以阐明疾病的发病机制,为治疗方法提供见解,并有助于开发改良的阿尔茨海默病动物模型。
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来源期刊
Ageing Research Reviews
Ageing Research Reviews 医学-老年医学
CiteScore
19.80
自引率
2.30%
发文量
216
审稿时长
55 days
期刊介绍: With the rise in average human life expectancy, the impact of ageing and age-related diseases on our society has become increasingly significant. Ageing research is now a focal point for numerous laboratories, encompassing leaders in genetics, molecular and cellular biology, biochemistry, and behavior. Ageing Research Reviews (ARR) serves as a cornerstone in this field, addressing emerging trends. ARR aims to fill a substantial gap by providing critical reviews and viewpoints on evolving discoveries concerning the mechanisms of ageing and age-related diseases. The rapid progress in understanding the mechanisms controlling cellular proliferation, differentiation, and survival is unveiling new insights into the regulation of ageing. From telomerase to stem cells, and from energy to oxyradical metabolism, we are witnessing an exciting era in the multidisciplinary field of ageing research. The journal explores the cellular and molecular foundations of interventions that extend lifespan, such as caloric restriction. It identifies the underpinnings of manipulations that extend lifespan, shedding light on novel approaches for preventing age-related diseases. ARR publishes articles on focused topics selected from the expansive field of ageing research, with a particular emphasis on the cellular and molecular mechanisms of the aging process. This includes age-related diseases like cancer, cardiovascular disease, diabetes, and neurodegenerative disorders. The journal also covers applications of basic ageing research to lifespan extension and disease prevention, offering a comprehensive platform for advancing our understanding of this critical field.
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