1)宁波大学医学部生理与病理学科,宁波 315211;2)宁波大学附属第一医院康复科,宁波 315211;3)宁波市康复医院科教科,宁波 315040
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浙江省自然科学基金(Y23H090004),浙江省省属高校基本科研业务费专项(SJLY2023008),宁波市自然科学基金(2023J068, 2022J035),国家自然科学基金(82001155),宁波市重点研发计划(2023Z173),浙江省医药卫生科技计划(2022KY1144),浙江省中医药科技计划(2023ZL162),宁波市教育规划课题一般项目(2023YGH003),宁波大学教研项目(JYXMXZD2023030),浙江省大学生科技创新活动计划(新苗人才计划)项目(2022R405A045,2024R405A069),宁波大学大学生科技创新计划(SRIP)项目(2024SRIP1904,2024SRIP1905)和高等学校学科创新引智基地(111计划)(D16013)资助。
1)Department of Physiology and Pharmacology, Health Science Centre, Ningbo University, Ningbo 315211, China;2)Rehabilitative Department, the First Affiliated Hospital of Ningbo University, Ningbo 315211, China;3)Department of Science and Education, Ningbo Rehabilitation Hospital, Ningbo 315040, China
This work was supported by grants from the Natural Science Foundation of Zhejiang Province (Y23H090004), the Fundamental Research Funds for the Provincial Universities of Zhejiang (SJLY2023008), the Natural Science Foundation of Ningbo (2023J068, 2022J035), The National Natural Science Foundation of China (82001155), Ningbo Key Research and Development Plan Project (2023Z173), the Medical Health Science and Technology Project of Zhejiang Provincial Health Commission (2022KY1144), Zhejiang Traditional Chinese Medicine Science and Technology Planning Project (2023ZL162), Ningbo Education Science Planning Project (2023YGH003), Ningbo University Teaching and Research Project (JYXMXZD2023030), College Students’ Scientific and Technological Innovation Project (Xin Miao Talent Plan) of Zhejiang Province (2022R405A045, 2024R405A069), the Student Research, Innovation Program (SRIP) of Ningbo University (2024SRIP1904, 2024SRIP1905), and National 111 Project of China (D16013).
阿尔茨海默病 (Alzheimer’s disease, AD) 是一种以进行性记忆减退、 认知障碍为主要临床表现的中枢神经系统退行性疾病。目前尚无有效手段治疗AD,近年来从不同方面探索治疗AD的手段,其中以清除β淀粉样蛋白(amyloid β-protein,Aβ)为靶点的药物治疗虽然在临床试验中取得突破性进展,但仍存在不良事件。神经炎症在AD的发病和进展中起着至关重要的作用。持续的神经炎症反应被认为是AD的第三大病理特征,可促进细胞外淀粉样斑块和细胞内神经纤维缠结形成,同时这些毒性物质又能加速神经炎症发展,形成恶性循环,加速疾病进展。通过改善神经炎症,从而打破神经炎症、Aβ斑块沉积、Tau缠结之间的反馈循环模式,可能成为一种治疗AD的有效途径。传统中草药如何首乌、姜黄,因其能够对抗神经炎症而被用于治疗AD;非甾体类抗炎药物布洛芬(Ibuprofen)、吲哚美辛(Indomethacin)等能降低体内炎症小体水平,服用非甾体类药物与AD低发病率存在关联;负载催产素的仿生纳米材料,具有抗吞噬作用,透过血脑屏障进入脑部持续释放催产素,发挥抗炎作用。间充质干细胞移植可降低神经炎症和抑制小胶质细胞活化,其分泌物不仅能改善神经炎症还具有多靶点综合治疗效果,可能更适于治疗AD。利用基因编辑技术靶向提高小胶质细胞中TREM2基因的表达,或应用 Ab-T1、hT2AB等TREM2抗体,可改善小胶质细胞功能,进而降低神经炎症水平,是一种治疗AD的潜在方法。益生元治疗、粪菌移植治疗、抗生素治疗、饮食干预等能重塑肠道菌群组成,通过肠-脑机制缓解神经炎症,但以低聚甘露糖酸钠为主的药物目前尚存争议。运动干预和脑电刺激干预均可潜在减缓神经炎症,可延缓AD。本文聚焦于近年来药物治疗、基因治疗、干细胞治疗、肠道菌群治疗、运动干预以及脑电刺激等方面在改善神经炎症中作用,以期为未来通过干预神经炎症作为治疗AD的方向提供新的思路。
Alzheimer’s disease (AD) is a central neurodegenerative disease characterized by progressive cognitive decline and memory impairment in clinical. Currently, there are no effective treatments for AD. In recent years, a variety of therapeutic approaches from different perspectives have been explored to treat AD. Although the drug therapies targeted at the clearance of amyloid β-protein (Aβ) had made a breakthrough in clinical trials, there were associated with adverse events. Neuroinflammation plays a crucial role in the onset and progression of AD. Continuous neuroinflammatory was considered to be the third major pathological feature of AD, which could promote the formation of extracellular amyloid plaques and intracellular neurofibrillary tangles. At the same time, these toxic substances could accelerate the development of neuroinflammation, form a vicious cycle, and exacerbate disease progression. Reducing neuroinflammation could break the feedback loop pattern between neuroinflammation, Aβ plaque deposition and Tau tangles, which might be an effective therapeutic strategy for treating AD. Traditional Chinese herbs such as Polygonum multiflorum and Curcuma were utilized in the treatment of AD due to their ability to mitigate neuroinflammation. Non-steroidal anti-inflammatory drugs such as ibuprofen and indomethacin had been shown to reduce the level of inflammasomes in the body, and taking these drugs was associated with a low incidence of AD. Biosynthetic nanomaterials loaded with oxytocin were demonstrated to have the capability to anti-inflammatory and penetrate the blood-brain barrier effectively, and they played an anti-inflammatory role via sustained-releasing oxytocin in the brain. Transplantation of mesenchymal stem cells could reduce neuroinflammation and inhibit the activation of microglia. The secretion of mesenchymal stem cells could not only improve neuroinflammation, but also exert a multi-target comprehensive therapeutic effect, making it potentially more suitable for the treatment of AD. Enhancing the level of TREM2 in microglial cells using gene editing technologies, or application of TREM2 antibodies such as Ab-T1, hT2AB could improve microglial cell function and reduce the level of neuroinflammation, which might be a potential treatment for AD. Probiotic therapy, fecal flora transplantation, antibiotic therapy, and dietary intervention could reshape the composition of the gut microbiota and alleviate neuroinflammation through the gut-brain axis. However, the drugs of sodium oligomannose remain controversial. Both exercise intervention and electromagnetic intervention had the potential to attenuate neuroinflammation, thereby delaying AD process. This article focuses on the role of drug therapy, gene therapy, stem cell therapy, gut microbiota therapy, exercise intervention, and brain stimulation in improving neuroinflammation in recent years, aiming to provide a novel insight for the treatment of AD by intervening neuroinflammation in the future.
单江晖,储超扬,陈是燏,林志成,周钰愉,方甜园,张楚霞,肖彪,谢凯,王清娟,刘志涛,李丽萍.不同干预手段改善神经炎症在治疗阿尔茨海默病中的效果分析[J].生物化学与生物物理进展,2025,52(2):310-333
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