Microglia - astrocyte cross-talk in the amyloid plaque niche of an Alzheimer’s disease mouse model as revealed by spatial transcriptomics (CosMx)

In this study, we characterize the transcriptomic alterations, cellular compositions, and signaling perturbations in the amyloid plaque niche in an AD mouse model using high-resolution spatial transcriptomics (CosMx and Stereo-seq). We discover a wide heterogeneity in the cellular composition of amyloid plaque niches, marked by an increase in microglial accumulation over time. We profile the alterations of glial cells as they are exposed to plaques, and conclude that the microglial response to plaques is consistent across different brain regions, while the astrocytic response is more heterogeneous. In turn, 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 neurons of the hippocampus. Taken together, we show that astrocytic signaling around plaque pathology is disrupted with increasing microglial density, which in turn induces an imbalance in synaptic signaling in neurons in the hippocampus. CosMx technology [CosMx Mouse Neuroscience Panel (950-plex); Nanostring, USA] was applied to the hippocampus and adjacent regions of AppNL-G-F KI mice at 18 months of age. Briefly, 10 µm thick tissue sections were fixed, antigen retrieval was performed and the tissue was permeabilized. Tissues from two mice were fixed onto each slide. In situ hybridisation was performed with the RNA mouse neuroscience panel, including the 18s RNA probe, and antibody morphology stain was performed with antibodies for Histone, glial fibrillary acidic protein (GFAP), 4′,6-diamidino-2-phenylindole (DAPI) and MOAB-2 for amyloid-β. Information from 84 FOV, with each FOV the size of 510 µm x 510 µm, were analyzed. After data acquisition, decoding of individual transcripts and segmentation of cells, based on Cellpose, was performed