Microglia-astrocyte crosstalk in the amyloid plaque niche of an Alzheimer's disease mouse model, as revealed by spatial transcriptomics

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. ; sponsorship: We would like to thank BGI for providing us with access and training to the Stereo-seq platform and for the continued collaboration, as well as VIB Technology Watch member Yu -Chun Wang for facilitating collaborations with BGI research. We would like to thank NanoString for making the CosMx experiment possible through the Technology Access Program and the Francis Crick Institute for funding this experiment. Thanks also goes to Tancredi Massimo Pentimalli, who inspired us to pursue neighborhood analyses by presenting his own CosMx analysis. This work is supported by the UK Dementia Research Institute (award number UK DRI-1004) , which receives its funding from UK DRI, Ltd., funded by the UK Medical Research Council, Alzheimer's Society, and Alzheimer's Research UK. In addition, a Medical Research Council Programme Grant (MR/Y014847/1) was awarded to B.D.S. and I.L.A.-C. The work was also funded by ...