PLCG2 is associated with the inflammatory response and is induced by amyloid plaques in Alzheimer’s disease

Abstract

AbstractBackgroundAlzheimer’s disease (AD) is characterized by robust microgliosis and phenotypic changes that accompany disease pathogenesis. Accumulating evidence from genetic studies suggests the importance of phospholipase C γ 2 (PLCG2) in late-onset AD (LOAD) pathophysiology. However, the role ofPLCG2in AD is still poorly understood.MethodsUsing bulk RNA-Seq (N=1249) data from the Accelerating Medicines Partnership-Alzheimer’s Disease Consortium (AMP-AD), we investigated whetherPLCG2expression increased in the brains of LOAD patients. We also evaluated the relationship betweenPLCG2expression levels, amyloid plaque density, and expression levels of microglia specific markers (AIF1 and TMEM119). Finally, we investigated the longitudinal changes ofPLCG2expression in the 5xFAD mouse model of AD. To further understand the role ofPLCG2in different signaling pathways, differential gene expression and co-expression network analyses were performed using bulk RNA-Seq and microglial single-cell RNA-Seq data. To substantiate the human analyses, we performed differential gene expression analysis on wild-type (WT) and inactivatedPlcg2mice and used immunostaining to determine if the differentially expressed genes/pathways were altered by microglial cell coverage or morphology.ResultsWe observed significant upregulation ofPLCG2expression in three brain regions of LOAD patients and significant positive correlation ofPLCG2expression with amyloid plaque density. These findings in the human brain were validated in the 5xFAD amyloid mouse model, which showed disease progression-dependent increases inPlcg2expression associated with amyloid pathology. Of note, increasedPlcg2expression levels in 5xFAD mice were abolished by reducing microglia. Furthermore, using bulk RNA-Seq data, we performed differential expression analysis by comparing cognitively normal older adults (CN) with 75th percentile (high) and 25th percentile (low)PLCG2gene expression levels to identify pathways related to inflammation and the inflammatory response. The findings in the human brain were validated by differential expression analyses between WT andplcg2inactivated mice.PLCG2co-expression network analysis of microglial single-cell RNA-Seq data identified pathways related to the inflammatory response including regulation of I-kappaB/NF-kappa B signaling and response to lipopolysaccharide.ConclusionsOur results provide further evidence thatPLCG2plays an important role in AD pathophysiology and may be a potential target for microglia-targeted AD therapies.