Department of Brain Sciences, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK.
UK Dementia Research Institute Centre, Imperial College London, London, UK.
Acta Neuropathol. 2024 May 2;147(1):78. doi: 10.1007/s00401-024-02727-9.
Aging is associated with cell senescence and is the major risk factor for AD. We characterized premature cell senescence in postmortem brains from non-diseased controls (NDC) and donors with Alzheimer's disease (AD) using imaging mass cytometry (IMC) and single nuclear RNA (snRNA) sequencing (> 200,000 nuclei). We found increases in numbers of glia immunostaining for galactosidase beta (> fourfold) and p16 (up to twofold) with AD relative to NDC. Increased glial expression of genes related to senescence was associated with greater β-amyloid load. Prematurely senescent microglia downregulated phagocytic pathways suggesting reduced capacity for β-amyloid clearance. Gene set enrichment and pseudo-time trajectories described extensive DNA double-strand breaks (DSBs), mitochondrial dysfunction and ER stress associated with increased β-amyloid leading to premature senescence in microglia. We replicated these observations with independent AD snRNA-seq datasets. Our results describe a burden of senescent glia with AD that is sufficiently high to contribute to disease progression. These findings support the hypothesis that microglia are a primary target for senolytic treatments in AD.
衰老是与细胞衰老相关的，是 AD 的主要风险因素。我们使用成像质谱细胞术（IMC）和单核 RNA（snRNA）测序（> 200,000 个核）对来自无疾病对照（NDC）和阿尔茨海默病（AD）供体的死后大脑中的过早细胞衰老进行了特征描述。与 NDC 相比，我们发现 AD 中半乳糖苷酶β（> 四倍）和 p16（高达两倍）的神经胶质免疫染色数量增加。与更高的 β-淀粉样蛋白负荷相关的与衰老相关的基因在神经胶质细胞中的表达增加。过早衰老的小胶质细胞下调吞噬途径，表明其清除 β-淀粉样蛋白的能力降低。基因集富集和拟时间轨迹描述了大量的 DNA 双链断裂（DSBs）、线粒体功能障碍和 ER 应激，这些与β-淀粉样蛋白的增加相关，导致小胶质细胞过早衰老。我们使用独立的 AD snRNA-seq 数据集复制了这些观察结果。我们的研究结果描述了 AD 中衰老的神经胶质细胞负担足够高，足以导致疾病进展。这些发现支持了小胶质细胞是 AD 中 senolytic 治疗的主要靶点的假说。
