Species: Mouse
Genes: Plcg2
Modification: Plcg2: Knock-In
Disease Relevance: Alzheimer's Disease, Dementia with Lewy Bodies, Frontotemporal Dementia
Strain Name: Plcg2^em1Bwef
Genetic Background: C57BL/6J
Availability: Available through Christian Haass.

Summary

The PLCG2 gene encodes the enzyme phospholipase C gamma 2 (PLCγ2), a mediator of transmembrane signaling in microglia that acts downstream of TREM2. A rare variant in this gene, P522R, has been associated with reduced risks of Alzheimer’s disease (Sims et al., 2017; Conway et al., 2018; van der Lee et al., 2019; Bellenguez et al., 2022), frontotemporal dementia (van der Lee et al., 2019), and dementia with Lewy bodies (van der Lee et al., 2019) (although it should be noted that other studies (Conway et al., 2018; Guerreiro et al., 2018; Orme et al., 2020; Strickland et al., 2020) did not find a statistically significant association with DLB). The P522R variant has also been reported to associate with less tau pathology in the brains of neuropathologically confirmed DLB and PSP cases (Strickland et al., 2020) and with increased longevity (van der Lee et al., 2019).

This knock-in model is homozygous for the P522R mutation in the endogenous mouse Plcg2 gene. Homozygous Plcγ2-P522R mice are viable, fertile, and do not show any overt abnormalities. However, the brains of these mice may appear to contain activated microglia and reactive astrocytes.

Transcriptomics

Gene expression was evaluated in brains harvested from 6-month-old male mice. The levels of several transcripts encoding proteins downstream of Plcγ2 signaling were elevated in the brains of Plcγ2-P522R mice, compared with wild-type animals. The expression levels of a subset of disease-associated microglial (DAM) genes (Keren-Shaul et al., 2017) were significantly elevated (Apoe) or showed a trend toward elevation (Cst7, Tyrobp, Clec7a, and Ccl3) in the brains of knock-in mice. The astrocytic marker Gfap and genes related to the neuronal cytoskeleton and myelination were also among those differentially expressed in knock-in and wild-type mice.

Gliosis

Hypertrophic astrocytes were seen in the hippocampi of Plcγ2-P522R mice. The number and morphology of microglia, revealed by immunostaining for the marker Iba1, did not differ in the brains of knock-in and wild-type mice. However, more cells stained for the purinergic receptor P2RY12, considered a marker of homeostatic microglia, in the cortices of Plcγ2-P522R mice.

Imaging biomarkers

TSPO PET imaging suggested microglial activation in the brains of year-old female knock-in mice. Glucose uptake did not differ between Plcγ2-P522R and wild-type mice in any brain region analyzed—whole brain, cortex, hippocampus, pons, and cerebellum. (Males were not used in these imaging studies.)

Modification Details

CRISPR/Cas9 was used to introduce the P522R mutation into the endogenous mouse Plcg2 gene. Knock-in mice were bred to homozygosity.

Phenotype Characterization

Complementary Models

Microglial-like cells derived from human induced pluripotent stem cell lines (hIPSCs) have been used to study PLCγ2 biology in human cells in vitro and in vivo after transplantation into mouse brains.

CRISPR/Cas9 gene editing was used to introduce the PLCG2 P522R mutation into hIPSCs derived from skin cells of an apparently healthy, middle-aged Caucasian male. Isogenic clones homozygous for the wild-type P522 allele or mutant R522 allele were differentiated into microglia-like cells (Maguire et al., 2021). Stimulation of PLCγ2 by Fc receptor ligation led to a greater increase in intracellular Ca²⁺ in cells carrying the mutant allele, consistent with a hypermorphic effect of the mutation. Similar to microglia and macrophages isolated from Plcg2*P522R knock-in mice (Maguire et al., 2021), hIPSC-derived microglia carrying the mutant allele showed decreased phagocytosis (uptake of E. coli particles or zymosan) and increased endocytosis (uptake of Aβ42 oligomers or Dextrans), compared with isogenic hIPSC-derived microglia expressing wild-type PLCγ2.

A second study compared isogenic hIPSC-derived microglia that differed with regard to P522R gene dose—wild-type (PLCγ2^WT), heterozygous for the P522R mutation (PLCγ2^HET), and homozygous for the  mutation (PLCγ2^HOM) (Solomon et al., 2022). In this case, the parental hIPSC line was derived from skin fibroblasts donated by a teenaged male (APOE3/4) of black or African-American ancestry with no diagnosed diseases. Here, too, CRISPR gene editing was used to introduce the PLCG2 P522R mutation. IPSC-derived microglia contained similar levels of PLCγ2 protein, regardless of PLCG2 genotype. However, the genotypes differed with regard to functional properties and gene expression—with PLCγ2^HET showing more pronounced differences than PLCγ2^HOM on several measures (compared with PLCγ2^WT). PLCγ2^HOM and PLCγ2^HET showed increased uptake of fluorescently labeled Aβ42, but only PLCγ2^HET cells showed increased uptake of Dextrans. Uptake of synaptosomes was reduced in P522R carriers, regardless of gene dose. LysoTracker staining—a marker for lysosomes—was elevated in P522R carriers, slightly more so in heterozygotes than homozygotes. When co-cultured with IPSC-derived neurons (heterozygous for the PLCG2 P522R mutation), PLCγ2^HET microglia engaged in less synaptic pruning—as measured by PSD95 engulfment—than PLCγ2^WT microglia, while PLCγ2^HOM did not significantly differ from PLCγ2^WT. When levels of expression of selected genes related to microglial function were compared between P522R carriers and wild-type cells, several genes were found to be upregulated in PLCγ2^HET—in pathways related to lipid metabolism, lysosomal biogenesis, and immune function—while only APOE was upregulated in PLCγ2^HOM. Microglial motility and intracellular Ca²⁺ levels were also greater in PLCγ2^HET compared with the other two PLCG2 genotypes. Physiological studies showed a gene-dose-dependent increase in oxidative phosphorylation with PLCγ2^HOM > PLCγ2^HET > PLCγ2^WT.

A third study focused on the effects of the P522R mutation on the transcriptomes of human microglia-like cells in vivo, in the context of amyloidosis (Claes et al., 2022). Once again, CRISPR gene editing was used to introduce the P522R mutation into the PLCG2 gene, this time in an (RFP)-α-tubulin expressing hIPSC line derived from fibroblasts donated by an apparently healthy 30-year-old Japanese man. IPSCs homozygous for the PLCG2 P522R mutation or isogenic hIPSCs with wild-type PLCG2 were differentiated into microglia-like cells in vitro, then grafted into the brains of neonatal immune-deficient 5xFAD or non-transgenic mice. Mice were aged to 7 months, a time when plaque deposition is well underway in 5xFAD brains, and the human cells were harvested for RNA sequencing. PLCG2 P522R microglia from 5xFAD brains showed increased levels of expression of multiple HLA and interferon genes and of genes encoding chemokines that mediate T-cell recruitment to the brain, compared with microglia expressing wild-type PLCG2. Gene Ontology analysis highlighted MHC class II antigen presentation, cytokine/chemokine signaling, interferon signaling, and regulation of T cell proliferation as pathways affected by the P522R mutation. PLCG2 P522R microglia isolated from non-transgenic hosts also showed increased expression of HLA genes, compared with microglia carrying wild-type PLCG2.

Chimeric 5xFAD brains were also examined histologically, and no differences were seen between those transplanted with P522R and wild-type PLCG2 hIPSC-derived microglia in the following measures: amyloid plaque burden, number, or size; microglial morphology, number of plaque-associated microglia, or microglial amyloid internalization; “amount” of plaque-associated dystrophic neurites; or numbers of total or plaque-associated astrocytes.

The lack of an effect of the P522R mutation on amyloid-related pathology in chimeric mice contrasted with findings in 5xFAD mice in which the P522R mutation was knocked into the endogenous Plcg2 gene. In the knock-in mice, the P522R mutation reduced amyloidosis, enhanced microglia-plaque interactions, and protected against plaque-associated pathology. The chimeric and knock-in models differ in several aspects that could potentially contribute to these discrepant findings, including intrinsic differences between human and mouse microglia, expression of P522R PLCγ2 in cells other than microglia in the knock-in mice, and lack of immune responses in chimeric hosts.

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References

Research Models Citations

1. Plcg2*P522R
2. 5xFAD (C57BL6)
3. Plcg2*P522R x 5xFAD

Paper Citations

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Other Citations

1. Christian Haass

External Citations

1. hIPSCs
2. hIPSC
3. hIPSC line

Further Reading