中国神经再生研究(英文版) ›› 2024, Vol. 19 ›› Issue (7): 1489-1498.doi: 10.4103/1673-5374.385847

• 综述:退行性病与再生 • 上一篇    下一篇

靶向tau治疗阿尔茨海默病:从机制到临床

  

  • 出版日期:2024-07-15 发布日期:2023-11-28
  • 基金资助:
    国家自然科学基金项目(82101493)

Targeting tau in Alzheimer’s disease: from mechanisms to clinical therapy

Jinwang Ye1, *, #, Huali Wan2, #, Sihua Chen1, Gong-Ping Liu3, 4, *   

  1. 1Shenzhen Key Laboratory of Marine Biotechnology and Ecology, College of Life Sciences and Oceanography, Shenzhen University, Shenzhen, Guangdong Province, China; 2Department of Laboratory Medicine, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong Province, China; 3Co-innovation Center of Neurodegeneration, Nantong University, Nantong, Jiangsu Province, China; 4Department of Pathophysiology, School of Basic Medicine and the Collaborative Innovation Center for Brain Science, Key Laboratory of Ministry of Education of China and Hubei Province for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
  • Online:2024-07-15 Published:2023-11-28
  • Contact: Gong-Ping Liu, PhD, liugp111@mail.hust.edu.cn; Jinwang Ye, yejinwang@szu.edu.cn.
  • Supported by:
    This work was supported by the National Natural Science Foundation of China, No. 82101493 (to JY).

摘要:

阿尔茨海默病影响老年人群最常见的神经退行性疾病,其主要的病理特征包括细胞外淀粉样蛋白β(Aβ)斑块聚集和细胞内tau蛋白形成的神经原纤维缠结积聚。已出现基于淀粉样蛋白β靶向疗法治疗阿尔茨海默病的方法,但其潜在的副作用以及昂贵的价格仍亟待解决。越来越多的证据表明,tau蛋白在阿尔茨海默病相关的神经退行性变中也具有重要的作用,且有临床研究显示,tau蛋白的异常磷酸化修饰发生在淀粉样蛋白β在大脑中积累之前。针对tau蛋白的各种治疗策略正在出现,这也被认为可能预防和治疗阿尔茨海默病。作为一种重要的微管相关蛋白,tau在维持神经元微管稳定性和促进轴突生长方面发挥着重要的作用。在阿尔茨海默病患者大脑中,tau蛋白可发生多种异常的翻译后修饰,如异常磷酸化、泛素化、苏木素化、乙酰化和截断等,而这些异常翻译后修饰可引发tau蛋白在细胞内的错误定位和异常聚集,从而导致线粒体功能障碍、突触可塑性受损、胶质细胞增生和神经炎症,最终引发神经退行性病变和认知功能障碍。此次综述总结了tau蛋白在阿尔茨海默病发生和发展中的潜在机制的最新发现,并讨论了靶向大脑内聚集的tau蛋白治疗阿尔茨海默病的研究进展。

https://orcid.org/0000-0001-8501-998X (Gong-Ping Liu)

关键词: 阿尔茨海默病, tau, 磷酸化, 乙酰化, 胶质细胞增生, 神经炎症, 线粒体损伤, 突触损伤, 认知障碍, 免疫疗法

Abstract: Alzheimer’s disease is the most prevalent neurodegenerative disease affecting older adults. Primary features of Alzheimer’s disease include extracellular aggregation of amyloid-β plaques and the accumulation of neurofibrillary tangles, formed by tau protein, in the cells. While there are amyloid-β-targeting therapies for the treatment of Alzheimer’s disease, these therapies are costly and exhibit potential negative side effects. Mounting evidence suggests significant involvement of tau protein in Alzheimer’s disease-related neurodegeneration. As an important microtubule-associated protein, tau plays an important role in maintaining the stability of neuronal microtubules and promoting axonal growth. In fact, clinical studies have shown that abnormal phosphorylation of tau protein occurs before accumulation of amyloid-β in the brain. Various therapeutic strategies targeting tau protein have begun to emerge, and are considered possible methods to prevent and treat Alzheimer’s disease. Specifically, abnormalities in post-translational modifications of the tau protein, including aberrant phosphorylation, ubiquitination, small ubiquitin-like modifier (SUMO)ylation, acetylation, and truncation, contribute to its microtubule dissociation, misfolding, and subcellular missorting. This causes mitochondrial damage, synaptic impairments, gliosis, and neuroinflammation, eventually leading to neurodegeneration and cognitive deficits. This review summarizes the recent findings on the underlying mechanisms of tau protein in the onset and progression of Alzheimer’s disease and discusses tau-targeted treatment of Alzheimer’s disease.

Key words: acetylation, Alzheimer’s disease, cognitive deficits, gliosis, mitochondria damage, neuroinflammation, phosphorylation, synaptic impairments, tau, tau immunotherapy