Amyloid-beta and tau pathologies act synergistically to induce novel disease stage-specific microglia subtypes.
Amyloid-beta and tau pathologies act synergistically to induce novel disease stage-specific microglia subtypes.
复制标题
DOI：
10.1186/s13024-022-00589-x
复制
发表时间：
2022-12-17
影响因子：
15.1
通讯作者：
中科院分区：
文献类型：
--
作者：
在与晚发性阿尔茨海默病（AD）相关的风险等位基因中，那些聚集在小胶质细胞活性调节上的等位基因已成为疾病进展的核心。然而，在AD的进展过程中，典型的淀粉样蛋白-β（A β）和tau病理如何调节小胶质细胞亚型仍然知之甚少。我们使用单细胞RNA测序来分析疾病进展过程中同时表现出A β和tau病理的小鼠的小胶质细胞亚型。我们确定了新的小胶质细胞亚型，这些亚型是以疾病阶段特异性的方式对A β和tau病理学做出反应而诱导的。为了验证AD小鼠模型中的观察结果，我们还从不同Braak阶段的人类上级额回（SFG）和内嗅皮层（ERC）生成snRNA-Seq数据集。我们发现，在早期疾病期间，干扰素信号传导诱导称为早期AD相关小胶质细胞（EADAM）的小胶质细胞亚型，以响应A β和tau病理。在晚期疾病期间，检测到称为晚期AD相关小胶质细胞（LADAM）的第二种小胶质细胞亚型。虽然在其他神经退行性疾病模型中观察到类似的小胶质细胞亚型，但在EADAM和LADAM中发现的基因特征的大小和组成是不同的，这表明A β和tau病理引起它们出现的必要性。重要的是，在AD脑的小胶质细胞中分别在疾病的早期（Braak II）或晚期（Braak VI/V）阶段观察到EADAM和LADAM相关基因表达的模式。此外，我们发现，几个Siglec基因在EADAM或LADAM中选择性表达。Siglecg在白质相关LADAM中表达，Siglecg的人类直系同源物Siglec-10的表达以AD阶段依赖性方式进行性升高，但在非AD tau蛋白病中未显示。在携带淀粉样蛋白-β和/或tau病理的小鼠模型中使用scRNA-Seq，我们以疾病阶段特异性方式鉴定了由A β和tau病理的组合诱导的新的小胶质细胞亚型。我们的研究结果表明，A β和tau病理都是EADAM和LADAM疾病阶段特异性诱导所必需的。此外，我们揭示了Siglecs作为AD进展的生物标志物和潜在的治疗靶点。 在线版本包含补充材料，可通过10.1186/s13024 - 022 - 00589-x获得。
Amongst risk alleles associated with late-onset Alzheimer’s disease (AD), those that converged on the regulation of microglia activity have emerged as central to disease progression. Yet, how canonical amyloid-β (Aβ) and tau pathologies regulate microglia subtypes during the progression of AD remains poorly understood. We use single-cell RNA-sequencing to profile microglia subtypes from mice exhibiting both Aβ and tau pathologies across disease progression. We identify novel microglia subtypes that are induced in response to both Aβ and tau pathologies in a disease-stage-specific manner. To validate the observation in AD mouse models, we also generated a snRNA-Seq dataset from the human superior frontal gyrus (SFG) and entorhinal cortex (ERC) at different Braak stages. We show that during early-stage disease, interferon signaling induces a subtype of microglia termed Early-stage AD-Associated Microglia (EADAM) in response to both Aβ and tau pathologies. During late-stage disease, a second microglia subtype termed Late-stage AD-Associated Microglia (LADAM) is detected. While similar microglia subtypes are observed in other models of neurodegenerative disease, the magnitude and composition of gene signatures found in EADAM and LADAM are distinct, suggesting the necessity of both Aβ and tau pathologies to elicit their emergence. Importantly, the pattern of EADAM- and LADAM-associated gene expression is observed in microglia from AD brains, during the early (Braak II)- or late (Braak VI/V)- stage of the disease, respectively. Furthermore, we show that several Siglec genes are selectively expressed in either EADAM or LADAM. Siglecg is expressed in white-matter-associated LADAM, and expression of Siglec-10, the human orthologue of Siglecg, is progressively elevated in an AD-stage-dependent manner but not shown in non-AD tauopathy. Using scRNA-Seq in mouse models bearing amyloid-β and/or tau pathologies, we identify novel microglia subtypes induced by the combination of Aβ and tau pathologies in a disease stage-specific manner. Our findings suggest that both Aβ and tau pathologies are required for the disease stage-specific induction of EADAM and LADAM. In addition, we revealed Siglecs as biomarkers of AD progression and potential therapeutic targets. The online version contains supplementary material available at 10.1186/s13024-022-00589-x.