Wang Yong-Chang, Huang Liang-Yu, Xiong Shi-Yin, Wang Zuo-Teng, Tan Chen-Chen, Tan Lan
Department of Neurology, Qingdao Municipal Hospital, Qingdao University, Qingdao, 266071, China.
Department of Neurology, Qingdao Hospital, University of Health and Rehabilitation Sciences (Qingdao Municipal Hospital), Qingdao, China.
J Transl Med. 2025 Jul 2;23(1):731. doi: 10.1186/s12967-025-06729-3.
The role of microglial activation by α-synuclein in Alzheimer’s disease (AD) remains unclear. This study aimed to evaluate the role of soluble triggering receptor expressed on myeloid cells 2 (sTREM2) in regulating the relationship between α-synuclein and tau pathology in cerebrospinal fluid (CSF).
A total of 989 participants were included in the CABLE (Chinese Alzheimer’s Biomarker and LifestylE) study. Multiple linear regression analyses were performed to assess the associations of CSF α-synuclein and sTREM2 with tau pathology. Causal mediation analyses with 10,000 bootstrap iterations were conducted to investigate the mediating effect of sTREM2 on the relationship between α-synuclein and tau pathology. Additionally, subgroup analyses were performed based on carrier status. The same analytical method was applied to the ADNI (Alzheimer’s Disease Neuroimaging Initiative) cohort for validation. Furthermore, Cox proportional hazards models were employed to evaluate the longitudinal association between α-synuclein levels and the risk of AD in the ADNI cohort. Causal mediation analysis further evaluated the mediating role of tau pathology in the relationship between α-synuclein and the risk of AD.
In CABLE, elevated levels of α-synuclein were significantly associated with increased levels of sTREM2 ( < 0.001), p-tau ( < 0.001), and T-tau ( < 0.001). The relationship between α-synuclein and tau pathology was partially mediated by sTREM2, with mediation rates of 4.8% and 6.3%, respectively. Further subgroup analysis revealed that this mediating relationship was present only in non-carriers. The CABLE findings were validated in the ADNI, with the proportion of mediators ranging from 17.1 to 18.8%. Additionally, higher levels of α-synuclein were linked to an increased risk of AD (hazard ratio = 2. 137, = 0.006). The relationship between α-synuclein levels and the risk of AD was mediated by p-tau but not T-tau, with a mediation rate of 67.6%.
Overall, activated microglia partially mediate the α-synuclein-tau pathology association, while p-tau further mediates the relationship between α-synuclein and AD risk. Thus, targeting the CSF α-synuclein-microglia-tau pathological pathway provides new insights into the prevention and treatment of AD.
The online version contains supplementary material available at 10.1186/s12967-025-06729-3.
α-突触核蛋白激活小胶质细胞在阿尔茨海默病（AD）中的作用尚不清楚。本研究旨在评估髓系细胞2上表达的可溶性触发受体（sTREM2）在调节脑脊液（CSF）中α-突触核蛋白与tau病理之间关系中的作用。
共有989名参与者纳入中国阿尔茨海默病生物标志物与生活方式（CABLE）研究。进行多元线性回归分析以评估脑脊液α-突触核蛋白和sTREM2与tau病理的关联。进行10000次自抽样迭代的因果中介分析，以研究sTREM2对α-突触核蛋白与tau病理之间关系的中介作用。此外，基于携带者状态进行亚组分析。将相同的分析方法应用于阿尔茨海默病神经影像学倡议（ADNI）队列进行验证。此外，采用Cox比例风险模型评估ADNI队列中α-突触核蛋白水平与AD风险的纵向关联。因果中介分析进一步评估tau病理在α-突触核蛋白与AD风险之间关系中的中介作用。
在CABLE研究中，α-突触核蛋白水平升高与sTREM2水平升高（P<0.001）、磷酸化tau蛋白（p-tau，P<0.001）和总tau蛋白（T-tau，P<0.001）显著相关。α-突触核蛋白与tau病理之间的关系部分由sTREM2介导，中介率分别为4.8%和6.3%。进一步的亚组分析显示，这种中介关系仅存在于非携带者中。CABLE研究结果在ADNI队列中得到验证，中介比例在17.1%至18.8%之间。此外，较高的α-突触核蛋白水平与AD风险增加相关（风险比=2.137，P=0.006）。α-突触核蛋白水平与AD风险之间的关系由p-tau介导，而非T-tau，中介率为67.6%。
总体而言，活化的小胶质细胞部分介导α-突触核蛋白-tau病理关联，而p-tau进一步介导α-突触核蛋白与AD风险之间的关系。因此，针对脑脊液α-突触核蛋白-小胶质细胞-tau病理途径为AD的预防和治疗提供了新的见解。
在线版本包含可在10.1186/s12967-025-06729-3获取的补充材料。
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