先天免疫基因在阿尔茨海默病中的作用。
The role of innate immune genes in Alzheimer's disease.
机构信息
Genetics and Aging Research Unit, McCance Center for Brain Health, Mass General Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, USA.
出版信息
Curr Opin Neurol. 2021 Apr 1;34(2):228-236. doi: 10.1097/WCO.0000000000000911.
PURPOSE OF REVIEW
The aim of this study was to provide an update on the role of the innate immune system and neuroinflammation in the pathogenesis of Alzheimer's disease, with an emphasis on microglial receptors CD33 and TREM2.
RECENT FINDINGS
Genome-wide association studies (GWAS) have identified many Alzheimer's disease risk genes related to immune response and microglia including the phagocytic receptors CD33 and TREM2. Recent GWAS and pathway analyses emphasize the crucial role of the innate immune system and neuroinflammation in the pathogenesis of Alzheimer's disease. Disease-associated microglia have been characterized by TREM2-dependent upregulation of phagocytic and lipid metabolism genes. Impaired microglial phagocytosis results in amyloid beta (Aβ) accumulation leading to neuroinflammation that is the primary cause of neurodegeneration. CD33 and TREM2 modulate neuroinflammation in Alzheimer's disease and have emerged as therapeutic targets in Alzheimer's disease. Progress has been made to inhibit CD33 by gene therapy, small molecules or immunotherapy, and to increase TREM2 activity by immunotherapy. Finally, mAbs against CD33 and TREM2 have entered clinical trials and may reduce neuroinflammation in Alzheimer's disease brain.
SUMMARY
Targeting neuroinflammation via CD33 inhibition and/or TREM2 activation may have important implications for neurodegeneration in Alzheimer's disease and may be an addition to monoclonal anti-Aβ antibody treatments that remove plaques without reducing neuroinflammation.
目的综述：本研究旨在介绍固有免疫系统和神经炎症在阿尔茨海默病发病机制中的作用，重点介绍小胶质细胞受体 CD33 和 TREM2。
最新发现：全基因组关联研究（GWAS）已确定许多与免疫反应和小胶质细胞相关的阿尔茨海默病风险基因，包括吞噬受体 CD33 和 TREM2。最近的 GWAS 和通路分析强调了固有免疫系统和神经炎症在阿尔茨海默病发病机制中的关键作用。与疾病相关的小胶质细胞表现为 TREM2 依赖性上调吞噬和脂质代谢基因。小胶质细胞吞噬作用受损导致淀粉样蛋白β（Aβ）积累，引发神经炎症，这是神经退行性变的主要原因。CD33 和 TREM2 调节阿尔茨海默病中的神经炎症，已成为阿尔茨海默病的治疗靶点。在通过基因治疗、小分子或免疫疗法抑制 CD33 以及通过免疫疗法增加 TREM2 活性方面已经取得了进展。最后，针对 CD33 和 TREM2 的 mAbs 已进入临床试验，可能会减少阿尔茨海默病大脑中的神经炎症。
总结：通过抑制 CD33 和/或激活 TREM2 来靶向神经炎症可能对阿尔茨海默病的神经退行性变具有重要意义，并且可能是添加到单克隆抗 Aβ 抗体治疗中的一种方法，这种方法可以清除斑块而不减少神经炎症。
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