Spatial Transcriptomics and In Situ Sequencing to Study Alzheimer’s Disease. Spatial Transcriptomics and In Situ Sequencing to Study Alzheimer’s Disease

While complex inflammatory-like alterations are observed around the amyloid plaques of Alzheimer disease (AD), little is known about the molecular changes and cellular interactions that characterize this response. We investigate here in an AD mouse model the transcriptional changes occurring in tissue domains of 100 μm diameter around the amyloid plaques using spatial transcriptomics. We demonstrate early alterations in a gene co-expression network enriched for myelin and oligodendrocyte genes (OLIG), while a multicellular gene co- expression network of Plaque-Induced Genes (PIGs) involving the complement system, oxidative stress, lysosomes and inflammation is prominent in the later phase of the disease. We confirm the majority of the observed alterations at the cellular level using in situ sequencing on mouse and human brain sections. Genome-wide spatial transcriptomic analysis provides an unprecedented approach to untangle the dysregulated cellular network in the vicinity of pathogenic hallmarks of AD and other brain diseases. Overall design: In situ 2D-RNAseq via Spatial Transcriptomics on coronal section of AppNL-G-F KI mice and C57Bl/6J mice at 3,6,12 and 18 months of age.