Jiao Hai-Shan, Ge Yi-Jun, Huang Liang-Yu, Liu Ying, Wu Bang-Sheng, Lian Piao-Piao, Hao Yi-Ning, Han Shan-Shan, Li Yi-Ting, Wu Kai-Min, Wu Chen-Yun, Cheng Tian-Lin, Yuan Peng, Yu Jin-Tai
Department of Neurology and National Center for Neurological Disorders, Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Shanghai Medical College, Fudan University, National Center for Neurological Disorders, 12Th Wulumuqi Zhong Road, Shanghai, 200040, China.
Department of Neurology, Qingdao Municipal Hospital, Qingdao University, Qingdao, China.
Mol Neurodegener. 2025 Aug 28;20(1):94. doi: 10.1186/s13024-025-00887-0.
Alzheimer's disease (AD) is the most common type of dementia. Genetic polymorphisms are associated with altered risks of AD onset, pointing to biological processes and potential targets for interventions. Consistent with the important roles of microglia in AD development, genetic mutations of several genes expressed on microglia have been identified as risks for AD. Emerging evidences indicate that the expression of a microglia-specific gene MS4A6A is thought to be associated with AD, since AD patients show upregulation of MS4A6A, and its levels correlate with the severity of clinical neuropathology. However, the mechanism linking MS4A6A and AD has not been experimentally studied.
We performed a meta genome-wide association analysis with 734,121 subjects to examine the associations between polymorphisms of MS4A6A with AD risks. In addition, we analyzed the correlation between MS4A6A and AD-related cerebrospinal fluid biomarkers from our own cohort. Furthermore, we for the first time generated a Ms4a6d deficient APP/PS1 model, and systematically examined pathological changes using high-resolution microscopy, biochemistry, and behavioral analysis.
We identified several new mutations of MS4A6A with altered AD risks, and discovered specific correlation for some of them with the amount of β-amyloid in cerebrospinal fluid. Protective variant of MS4A6A is associated with elevated expression of the gene. Deficient Ms4a6d led to reduced amyloid clearance in the brain. Immunostaining from postmortem AD patients brain revealed selective expression of MS4A6A in microglia. In APP/PS1 mice lacking Ms4a6d, microglia showed markedly diminished envelopment and phagocytosis of amyloid, leading to increased plaque burden, less compact structure, and more severe synaptic damage. Importantly, Ms4a6d deficiency markedly exacerbated inflammatory responses in both microglia and astrocytes by disinhibiting NF-κB signaling. Overexpressing MS4A6A in human microglia cell line promoted gene expression related to plaque-associated responses and diminished inflammation signatures.
Our findings reveal that Ms4a6d deficiency suppresses neuroprotection and worsens neuroinflammation. Sufficient Ms4a6d maybe beneficial for boosting amyloid-related responses and suppressing inflammation in microglia, making it superior than previously reported candidates for microglia modulation. Thus, the elevated MS4A6A levels in AD are likely compensatory and boosting MS4A6A could be an effective treatment.
阿尔茨海默病（AD）是最常见的痴呆类型。基因多态性与AD发病风险的改变相关，提示了生物学过程及潜在的干预靶点。与小胶质细胞在AD发展中的重要作用一致，已确定小胶质细胞上表达的几个基因的基因突变是AD的风险因素。新出现的证据表明，小胶质细胞特异性基因MS4A6A的表达被认为与AD相关，因为AD患者中MS4A6A表达上调，且其水平与临床神经病理学的严重程度相关。然而，MS4A6A与AD之间的联系机制尚未进行实验研究。
我们对734,121名受试者进行了全基因组关联分析，以研究MS4A6A多态性与AD风险之间的关联。此外，我们分析了来自我们自己队列的MS4A6A与AD相关脑脊液生物标志物之间的相关性。此外，我们首次构建了Ms4a6d缺陷的APP/PS1模型，并使用高分辨率显微镜、生物化学和行为分析系统地检查了病理变化。
我们鉴定出了几种新的MS4A6A突变，其AD风险发生改变，并发现其中一些与脑脊液中β-淀粉样蛋白的量存在特定相关性。MS4A6A的保护性变体与该基因的表达升高相关。Ms4a6d缺陷导致大脑中淀粉样蛋白清除减少。对AD患者死后大脑进行免疫染色显示，MS4A6A在小胶质细胞中有选择性表达。在缺乏Ms4a6d的APP/PS1小鼠中，小胶质细胞对淀粉样蛋白的包裹和吞噬作用明显减弱，导致斑块负担增加、结构疏松程度降低以及更严重的突触损伤。重要的是，Ms4a6d缺陷通过解除对NF-κB信号通路的抑制，显著加剧了小胶质细胞和星形胶质细胞中的炎症反应。在人小胶质细胞系中过表达MS4A6A可促进与斑块相关反应的基因表达，并减少炎症特征。
我们的研究结果表明，Ms4a6d缺陷会抑制神经保护并加重神经炎症。充足的Ms4a6d可能有利于增强与淀粉样蛋白相关的反应并抑制小胶质细胞中的炎症，使其比先前报道的小胶质细胞调节候选物更具优势。因此，AD中MS4A6A水平升高可能是一种代偿，提高MS4A6A水平可能是一种有效的治疗方法。
