Loss of Inpp5d has disease‐relevant and sex‐specific effects on glial transcriptomes

Abstract INTRODUCTION Inpp5d is genetically associated with Alzheimer's disease risk. Loss of Inpp5d alters amyloid pathology in models of amyloidosis. Inpp5d is expressed predominantly in microglia but its function in brain is poorly understood. METHODS We performed single‐cell RNA sequencing to study the effect of Inpp5d loss on wild‐type mouse brain transcriptomes. RESULTS Loss of Inpp5d has sex‐specific effects on the brain transcriptome. Affected genes are enriched for multiple neurodegeneration terms. Network analyses reveal a gene co‐expression module centered around Inpp5d in female mice. Inpp5d loss alters Pleotrophin (PTN), Prosaposin (PSAP), and Vascular Endothelial Growth Factor A (VEGFA) signaling probability between cell types. DISCUSSION Our data suggest that the normal function of Inpp5d is entangled with mechanisms involved in neurodegeneration. We report the effect of Inpp5d loss without pathology and show that this has dramatic effects on gene expression. Our study provides a critical reference for researchers of neurodegeneration, allowing separation of disease‐specific changes mediated by Inpp5d in disease from baseline effects of Inpp5d loss. Highlights Loss of Inpp5d has different effects in male and female mice. Genes dysregulated by Inpp5d loss relate to neurodegeneration. Total loss of Inpp5d in female mice collapses a conserved gene co‐expression module. Loss of microglial Inpp5d affects the transcriptome of other cell types.