The P522R protective variant of PLCG2 promotes the expression of antigen presentation genes by human microglia in an Alzheimer's disease mouse model

Claes, Christel; England, Whitney; Danhash, Emma; Shabestari, Sepideh Kiani; Jairaman, Amit; Chadarevian, Jean Paul; Hasselmann, Jonathan; Tsai, Andy Po‐Yi; Coburn, Morgan A.; Sanchez, Jessica; Lim, Tau En; Hidalgo, Jorge Luis Silva; Tu, Christina H.; Cahalan, Michael D.; Lamb, Bruce T.; Landreth, Gary E.; Spitale, Robert C.; Blurton‐Jones, Mathew

doi:10.1002/alz.12577

Cited by 33 publications

(26 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our single-nuclei RNA-seq analysis data indicated that PLCG2 variants regulate the composition of microglial clusters in the AD brain. These results were consistent with our previous analysis of AD chimeric mice with xenografted human iPSC-derived microglia expressing PLCG2 P522R (Claes et al, 2022), in which the proportions of microglia enriched in Spp1, Fabp5, and Cd74 were elevated. Moreover, 5xFAD P522R mice exhibit a plaqueresponsive microglial subcluster enriched in Hcar2, a microglial receptor we recently identified to be required for efficient and neuroprotective microglial responses to amyloid pathology (Moutinho et al, 2022).…”

Section: Discussionsupporting

confidence: 93%

Genetic Variants of Phospholipase C-γ2 Confer Altered Microglial Phenotypes and Differential Risk for Alzheimer’s Disease

Tsai

Dong

Lin

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

Genetic association studies have demonstrated the critical involvement of the microglial immune response in Alzheimers disease (AD) pathogenesis. Phospholipase C-gamma-2 (PLCG2) is selectively expressed by microglia and acts in many immune receptor signaling pathways. In AD, PLCG2 is induced uniquely in plaque-associated microglia. A genetic variant of PLCG2, PLCG2 P522R variant, is a mild hypermorph that attenuates AD risk. We report the identification of a PLCG2 variant, PLCG2 M28L variant, associated with loss-of-function and confers increased AD risk. PLCG2 P522R variant attenuates disease in an amyloidogenic murine AD model, whereas PLCG2 M28L variant exacerbates the plaque burden associated with altered phagocytosis and Aβ clearance. The variants bidirectionally modulate disease pathology by inducing distinct transcriptional programs that identify microglial subpopulations associated with protective or detrimental phenotypes. In summary, these findings identify PLCG2 M28L variant as a new AD risk variant and demonstrate that PLCG2 variants can differentially orchestrate microglial responses in AD pathogenesis that can be therapeutically targeted.

show abstract

Section: Discussionsupporting

confidence: 93%

Genetic Variants of Phospholipase C-γ2 Confer Altered Microglial Phenotypes and Differential Risk for Alzheimer’s Disease

Tsai

Dong

Lin

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…Recent studies have suggested that the P522R variant is a mild hypermorph [ 15 – 17 ], serving to potentiate the enzymatic activity of the protein, thus impacting on its downstream targets. It has been shown that this altered activity appears to enhance macrophage phagocytic activity and enhance cytokine release in response to inflammatory stimulation, and may promote microglial activation [ 17 ], priming them to adopt an MHC class II state, that is notably reduced in AD brains [ 18 ]. Conversely however, other studies have suggested that in fact phagocytic clearance is impaired, while endocytic clearance is enhanced [ 15 ], hence its exact impact on phagocytic vs. endocytic clearance of AD relevant cargoes is still unclear.…”

Section: Introductionmentioning

confidence: 99%

Heterozygous expression of the Alzheimer’s disease-protective PLCγ2 P522R variant enhances Aβ clearance while preserving synapses

Solomon

Sampathkumar

Carre

et al. 2022

Cell. Mol. Life Sci.

View full text Add to dashboard Cite

Background A rare coding variant, P522R, in the phospholipase C gamma 2 (PLCG2) gene has been identified as protective against late-onset Alzheimer’s disease (AD), but the mechanism is unknown. PLCG2 is exclusively expressed in microglia within the central nervous system, and altered microglial function has been implicated in the progression of AD. Methods Healthy control hiPSCs were CRISPR edited to generate cells heterozygous and homozygous for the PLCG2P522R variant. Microglia derived from these hiPSC’s were used to investigate the impact of PLCγ2P522R on disease relevant processes, specifically microglial capacity to take up amyloid beta (Aβ) and synapses. Targeted qPCR assessment was conducted to explore expression changes in core AD linked and microglial genes, and mitochondrial function was assessed using an Agilent Seahorse assay. Results Heterozygous expression of the P522R variant resulted in increased microglial clearance of Aβ, while preserving synapses. This was associated with the upregulation of a number of genes, including the anti-inflammatory cytokine Il-10, and the synapse-linked CX3CR1, as well as alterations in mitochondrial function, and increased cellular motility. The protective capacity of PLCγ2P522R appeared crucially dependent on (gene) ‘dose’, as cells homozygous for the variant showed reduced synapse preservation, and a differential gene expression profile relative to heterozygous cells. Conclusion These findings suggest that PLCγ2P522R may result in increased surveillance by microglia, and prime them towards an anti-inflammatory state, with an increased capacity to respond to increasing energy demands, but highlights the delicate balance of this system, with increasing PLCγ2P522R ‘dose’ resulting in reduced beneficial impacts. Graphical abstract

show abstract

“…A PLCγ2-P522R knock-in mouse model was established to assess the role of the protective variant in immune cells, which showed that the PLCγ2-P522R variant promoted microglial immune functions [90]. Besides, the PLCγ2-P522R variant increases the capacity of human microglia to present antigens and promoted the recruitment of CD8 + T cells to the brain in AD mouse models [91]; however, the role of the PLCγ2-P522R variant in the crosstalk between microglia and T cells in AD requires further study.…”

Section: Phospholipase C Gamma 2 (Plcg2)mentioning

confidence: 99%

Pathogenesis, therapeutic strategies and biomarker development based on “omics” analysis related to microglia in Alzheimer’s disease

Gao

Shen

Tan

et al. 2022

J Neuroinflammation

View full text Add to dashboard Cite

Alzheimer’s disease (AD) is the most common neurodegenerative disease and the most common cause of dementia. Among various pathophysiological aspects, microglia are considered to play important roles in the pathogenesis of AD. Genome wide association studies (GWAS) showed that the majority of AD risk genes are highly or exclusively expressed in microglia, underscoring the critical roles of microglia in AD pathogenesis. Recently, omics technologies have greatly advanced our knowledge of microglia biology in AD. Omics approaches, including genomics, epigenomics, transcriptomics, proteomics, and metabolomics/lipidomics, present remarkable opportunities to delineate the underlying mechanisms, discover novel diagnostic biomarkers, monitor disease progression, and shape therapeutic strategies for diseases. In this review, we summarized research based on microglial “omics” analysis in AD, especially the recent research advances in the identification of AD-associated microglial subsets. This review reinforces the important role of microglia in AD and advances our understanding of the mechanism of microglia in AD pathogenesis. Moreover, we proposed the value of microglia-based omics in the development of therapeutic strategies and biomarkers for AD.

show abstract

The P522R protective variant of PLCG2 promotes the expression of antigen presentation genes by human microglia in an Alzheimer's disease mouse model

Cited by 33 publications

References 48 publications

Genetic Variants of Phospholipase C-γ2 Confer Altered Microglial Phenotypes and Differential Risk for Alzheimer’s Disease

Genetic Variants of Phospholipase C-γ2 Confer Altered Microglial Phenotypes and Differential Risk for Alzheimer’s Disease

Heterozygous expression of the Alzheimer’s disease-protective PLCγ2 P522R variant enhances Aβ clearance while preserving synapses

Pathogenesis, therapeutic strategies and biomarker development based on “omics” analysis related to microglia in Alzheimer’s disease

Contact Info

Product

Resources

About