Analyses of Nogo-Family Genes in Mouse and Human Microglia Omics Datasets Identify LINGO1 as a Candidate Drug Target in Alzheimer’s Disease

Abstract

Microglia are the innate immune cells of the brain. Recent single cell and nucleus sequencing along with other omics technologies are leading the way for new discoveries related to microglial function and diversity. The Nogo-signaling system is a prime target for investigation with these tools as it has previously been neglected in microglia. The Nogo-signaling system consists of approximately 20 proteins, including ligands, receptors, co-receptors, and endogenous inhibitors known for their neuronal plasticity restricting properties via RhoA and ROCK1/ROCK2 activation, and have recently been implicated in microglial function. Here, we explore expression patterns of Nogo-family genes in the mouse and human brain. In mice, we focus on brain cell type enrichment, patterns of expression in microglia from embryonic stages to adulthood, sex differences, and changes in expression in acute and chronic inflammatory contexts from publicly available RNAseq and RiboTag translational profiling datasets. We identified differential expression of Nogo-family genes across age, sex, and disease/injury in mice. To analyze human microglia, we utilize a new tool, the CZ CellxGene Discover, to aggregate 21 single cell sequencing datasets of human brain cells in Alzheimer’s (AD) and control patients. In humans, LINGO1 is highly enriched in human AD microglia, a previously undescribed finding. We used The Alzheimer’s Cell Atlas (TACA) to further verify if this enrichment correlates to disease state, severity of human AD diagnosis, or sex of patients. The current work provides a comprehensive analysis of Nogo-family genes in microglia and identifies LINGO1 as a potential therapeutic target for AD.