Highlights d Exposure to Ab in AD potentiates a microglia response present during normal aging d This microglia response is heterogeneous with potential synaptotoxic subtypes d Microglia in female mice develop this response faster than in male mice d Apoe deletion blocks the main response of microglia to Ab
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 coexpression 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.
While genetics highlight the role of microglia in Alzheimer's disease (AD), one third of putative AD-risk genes lack adequate mouse orthologs. Here, we successfully engraft human microglia derived from embryonic stem cells in the mouse brain. The cells recapitulate transcriptionally human primary microglia ex vivo and show expression of human specific AD-risk genes. Oligomeric Amyloid-β induces a divergent response in human vs. mouse microglia. This model can be used to study the role of microglia in neurological diseases.
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