Department of Immunology, CAMS Key laboratory T cell and Cancer Immunotherapy, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, State Key Laboratory of Common Mechanism Research for Major Diseases, Beijing 100005, China; Research Unit of Diagnosis and Treatment of Chronic Nasal Diseases, Chinese Academy of Medical Sciences, Beijing, China.
Department of Immunology, CAMS Key laboratory T cell and Cancer Immunotherapy, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, State Key Laboratory of Common Mechanism Research for Major Diseases, Beijing 100005, China.
Ageing Res Rev. 2024 Nov;101:102471. doi: 10.1016/j.arr.2024.102471. Epub 2024 Aug 31.
Alzheimer's disease is a chronic degenerative disease of the central nervous system, which primarily affects elderly people and accounts for 70-80 % of dementia cases. The current prevailing amyloid cascade hypothesis suggests that Alzheimer's disease begins with the deposition of amyloid β (Aβ) in the brain. Major therapeutic strategies target Aβ production, aggregation, and clearance, although many clinical trials have shown that these therapeutic strategies are not sufficient to completely improve cognitive deficits in AD patients. Recent genome-wide association studies have identified that multiple important regulators are the most significant genetic risk factors for Alzheimer's disease, especially in the innate immune pathways. These genetic risk factors suggest a critical role for microglia, highlighting their therapeutic potential in treating neurodegenerative diseases. In this review, we discuss how these recently documented AD risk genes affect microglial function and AD pathology and how they can be further targeted to regulate microglial states and slow AD progression, especially the highly anticipated APOE and TREM2 targets. We focused on recent findings that modulation of innate and adaptive neuroimmune microenvironment crosstalk reverses cognitive deficits in AD patients. We also considered novel strategies for microglia in AD patients.
阿尔茨海默病是一种中枢神经系统的慢性退行性疾病，主要影响老年人，占痴呆症病例的 70-80%。目前流行的淀粉样蛋白级联假说认为，阿尔茨海默病始于大脑中淀粉样蛋白β (Aβ) 的沉积。主要的治疗策略针对 Aβ 的产生、聚集和清除，但许多临床试验表明，这些治疗策略不足以完全改善 AD 患者的认知缺陷。最近的全基因组关联研究表明，多种重要的调节因子是阿尔茨海默病最重要的遗传风险因素，特别是在先天免疫途径中。这些遗传风险因素表明小胶质细胞起着关键作用，突出了它们在治疗神经退行性疾病方面的治疗潜力。在这篇综述中，我们讨论了这些最近记录的 AD 风险基因如何影响小胶质细胞功能和 AD 病理学，以及如何进一步针对这些基因来调节小胶质细胞状态和减缓 AD 进展，特别是备受期待的 APOE 和 TREM2 靶点。我们重点关注了最近的发现，即调节先天和适应性神经免疫微环境的串扰可以逆转 AD 患者的认知缺陷。我们还考虑了针对 AD 患者的小胶质细胞的新策略。
