Abstract：
The amyloid plaque niche is a pivotal hallmark of Alzheimer\'s disease (AD). Here, we employ two high-resolution spatial transcriptomics (ST) platforms, CosMx and Spatial Enhanced Resolution Omics-sequencing (Stereo-seq), to characterize the transcriptomic alterations, cellular compositions, and signaling perturbations in the amyloid plaque niche in an AD mouse model. We discover heterogeneity in the cellular composition of plaque niches, marked by an increase in microglial accumulation. We profile the transcriptomic alterations of glial cells in the vicinity of plaques and conclude that the microglial response to plaques is consistent across different brain regions, while the astrocytic response is more heterogeneous. Meanwhile, as the microglial density of plaque niches increases, astrocytes acquire a more neurotoxic phenotype and play a key role in inducing GABAergic signaling and decreasing glutamatergic signaling in hippocampal neurons. We thus show that the accumulation of microglia around hippocampal plaques disrupts astrocytic signaling, in turn inducing an imbalance in neuronal synaptic signaling.
摘要：
淀粉样蛋白斑块小生境是阿尔茨海默病(AD)的重要标志。这里,我们使用两个高分辨率空间转录组学(ST)平台，CosMx和空间增强分辨率组学测序(Stereo-seq)，来表征转录组改变，细胞成分，和AD小鼠模型中淀粉样蛋白斑块生态位的信号扰动。我们发现斑块壁龛细胞组成的异质性，以小胶质细胞积累的增加为标志。我们分析了斑块附近神经胶质细胞的转录变化，并得出结论，小胶质细胞对斑块的反应在不同的大脑区域是一致的。而星形细胞的反应更为异质。同时,随着斑块壁龛的小胶质细胞密度增加，星形胶质细胞获得更多的神经毒性表型,并在诱导GABA能信号传导和减少海马神经元的谷氨酸能信号传导中起关键作用.因此，我们表明海马斑块周围小胶质细胞的积累破坏了星形胶质细胞信号，进而诱导神经元突触信号的失衡。
