Kosoy Roman, Fullard John F, Bendl Jaroslav, Kleopoulos Steven P, Shao Zhiping, Argyriou Stathis, Mathur Deepika, Psychogyiou Konstantina, Malakates Periklis, Vicari James, Ma Yixuan, Humphrey Jack, Brophy Erica, Raj Towfique, Katsel Pavel, Voloudakis Georgios, Lee Donghoon, Bennett David A, Haroutunian Vahram, Hoffman Gabriel E, Roussos Panos
Center for Disease Neurogenomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Nat Neurosci. 2025 Aug 4. doi: 10.1038/s41593-025-02020-2.
Microglia are resident immune cells of the brain and are implicated in the etiology of Alzheimer's disease (AD) and other diseases. Yet the cellular and molecular processes regulating their function throughout the course of the disease are poorly understood. Here, we present a transcriptional analysis of primary microglia from 189 human postmortem brains, including 58 healthy aging individuals and 131 with a range of disease phenotypes, such as 63 patients representing the full clinical and pathological spectra of AD. We identified changes associated with multiple AD phenotypes, capturing the severity of dementia and neuropathological lesions. Transcript-level analyses identified additional genes with heterogeneous isoform usage and AD phenotypes. We identified changes in gene-gene coordination in AD, dysregulation of coexpression modules and disease subtypes with distinct gene expression patterns. Taken together, these data further our understanding of the key role that microglia have in AD biology and nominate candidates for therapeutic intervention.
小胶质细胞是大脑中的常驻免疫细胞，与阿尔茨海默病（AD）及其他疾病的病因有关。然而，在疾病发展过程中调节其功能的细胞和分子过程仍知之甚少。在此，我们对来自189例人类死后大脑的原代小胶质细胞进行了转录分析，其中包括58名健康老年人和131名具有一系列疾病表型的个体，如63例代表AD完整临床和病理谱的患者。我们确定了与多种AD表型相关的变化，涵盖痴呆症的严重程度和神经病理损伤。转录水平分析确定了具有异质异构体使用情况和AD表型的其他基因。我们发现了AD中基因-基因协调的变化、共表达模块的失调以及具有不同基因表达模式的疾病亚型。综上所述，这些数据进一步加深了我们对小胶质细胞在AD生物学中的关键作用的理解，并为治疗干预提名了候选对象。
