PLCG2 deficiency alters the neuroinflammatory transcriptome and sickness behavior response to LPS 9336

Abstract Description PLCG2, a critical immune regulator, has emerged as a key factor in Alzheimer’s disease, with genetic variants conferring both risk and protection. In the brain, PLCG2 is mainly expressed in microglia, influencing cellular functions including calcium signaling. We investigated PLCG2’s role in neuroinflammation using constitutive and inducible knockout mouse models with LPS-induced acute inflammation. In the constitutive KO, LPS treatment induced >200 differentially expressed genes in the brain, altering pathways related to innate and adaptive immune responses, inflammatory signaling, and microglial function. KO mice exhibited a distinct gene signature in response to LPS, with upregulated genes associated with interleukin signaling, prostaglandin response, and interferon pathways. Interferon-responsive genes were upregulated in homozygote KO mice post-LPS treatment, a phenotype that has been linked to white matter pathology. Consistently, principal component analysis of myelin-enriched genes revealed LPS-treated homozygote KO samples clustering separately from other genotypes. Behaviorally, LPS-treated KO mice displayed reduced locomotion in open field tests, correlating with expression of sickness behavior-related genes. These findings suggest PLCG2 deficiency enhances interferon responses, potentially driving behavioral changes and myelin pathology phenotypes. Inducible KO mice showed distinct behavior, with ongoing efforts focused on assessing their brain transcriptomes. Funding Sources This research was supported by the Alzheimer’s Association (AARG-21-846012, SH and JPP) the William and Ella Owens Medical Research Foundation (JPP), and intramural funding (SH and JPP). Topic Categories Neuroimmunology (NEUR)