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

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References

Paper Citations

1. 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Other Citations

1. Christian Haass

Further Reading