Department of Biomedical Sciences of Cells and Systems, Section Molecular Neurobiology, University of Groningen and University Medical Center Groningen (UMCG), Antonius Deusinglaan 1, 9713AV, Groningen, the Netherlands.
Foundational Neuroscience Center, AbbVie Inc, Cambridge, MA, USA.
Acta Neuropathol. 2021 May;141(5):681-696. doi: 10.1007/s00401-021-02263-w. Epub 2021 Feb 20.
Alzheimer's disease (AD) is the most prevalent form of dementia and is characterized by abnormal extracellular aggregates of amyloid-β and intraneuronal hyperphosphorylated tau tangles and neuropil threads. Microglia, the tissue-resident macrophages of the central nervous system (CNS), are important for CNS homeostasis and implicated in AD pathology. In amyloid mouse models, a phagocytic/activated microglia phenotype has been identified. How increasing levels of amyloid-β and tau pathology affect human microglia transcriptional profiles is unknown. Here, we performed snRNAseq on 482,472 nuclei from non-demented control brains and AD brains containing only amyloid-β plaques or both amyloid-β plaques and tau pathology. Within the microglia population, distinct expression profiles were identified of which two were AD pathology-associated. The phagocytic/activated AD1-microglia population abundance strongly correlated with tissue amyloid-β load and localized to amyloid-β plaques. The AD2-microglia abundance strongly correlated with tissue phospho-tau load and these microglia were more abundant in samples with overt tau pathology. This full characterization of human disease-associated microglia phenotypes provides new insights in the pathophysiological role of microglia in AD and offers new targets for microglia-state-specific therapeutic strategies.
阿尔茨海默病（AD）是最常见的痴呆症形式，其特征是细胞外淀粉样蛋白-β异常聚集和神经元内过度磷酸化的 tau 缠结和神经丝。小胶质细胞是中枢神经系统（CNS）的组织驻留巨噬细胞，对 CNS 稳态很重要，并与 AD 病理学有关。在淀粉样蛋白小鼠模型中，已经确定了吞噬/激活的小胶质细胞表型。增加的淀粉样蛋白-β和 tau 病理学如何影响人类小胶质细胞转录谱尚不清楚。在这里，我们对 482,472 个来自非痴呆对照大脑和仅含有淀粉样蛋白-β斑块或淀粉样蛋白-β斑块和 tau 病理学的 AD 大脑的核进行了 snRNAseq 分析。在小胶质细胞群体中，确定了两个与 AD 病理学相关的独特表达谱。吞噬/激活的 AD1-小胶质细胞群体丰度与组织淀粉样蛋白-β负荷强烈相关，并定位于淀粉样蛋白-β斑块中。AD2-小胶质细胞的丰度与组织磷酸化 tau 负荷强烈相关，这些小胶质细胞在明显有 tau 病理学的样本中更为丰富。这种对人类疾病相关小胶质细胞表型的全面描述为小胶质细胞在 AD 中的病理生理作用提供了新的见解，并为小胶质细胞状态特异性治疗策略提供了新的靶点。
