Gpnmb? Microglia Represent a Distinct Subtype Reacting to Neuronal Loss induced by Prion Disease

Of all neurodegenerative pathologies, prion diseases exhibit one of the most extensive neuroinflammatory phenotypes, yet the impact of neuroinflammation on the course of the disease is anything but clear . Prions trigger conspicuous proliferation of microglial cells, which may contribute to neuronal damage but are also involved in prion clearance . We approached these questions by establishing a spatial-transcriptomic atlas of the progression of prion disease, and identified GPNMB gene as the most enriched one in a subset of microglial cells with enhanced phagocytic activity present only in prion-infected mice. This cell type responded to ongoing apoptosis in distinct brain regions from 30 weeks post-prion inoculation and progressively increased up to the terminal stage of the disease. Overall design: Prion infected animals (RML6) and related (NBH) controls were sacrificed at 3 different timepoints during disease progression: 27 weeks post intraperitoneal injection (wpi), 30 wpi and terminal stage. OCT embedded brains were cut to generate 10 um thin-cryosections. Spatial transcriptomics was then performed by using 10x Genomics protocol.在所有神经退行性病变中，朊病毒疾病（prion diseases）展现出最为显著的神经炎症表型之一，然而神经炎症对疾病进程的影响却远未阐明。朊病毒可引发小胶质细胞（microglial cells）的显著增殖，这一过程或参与神经元损伤，同时也参与朊病毒的清除过程。本研究通过构建朊病毒疾病进程的空间转录组图谱（spatial-transcriptomic atlas）来解答上述问题，并鉴定出GPNMB基因是仅存在于朊病毒感染小鼠中、具有增强吞噬活性的特定小胶质细胞亚群中富集程度最高的基因。该细胞群自朊病毒接种后30周起，即可对不同脑区内持续发生的细胞凋亡产生应答，并随疾病进展逐渐增多，直至疾病终末期。实验设计概述：分别在疾病进程的3个时间点处死朊病毒感染组动物（RML6）及同源对照（NBH）：腹腔注射后27周（wpi）、30 wpi以及疾病终末期。将OCT包埋的脑组织制备为10 μm厚冰冻切片，随后采用10x Genomics实验流程进行空间转录组测序。