Species: Mouse
Genes: Plcg2, App
Mutations: APP K670_M671delinsNL (Swedish), APP I716F (Iberian), APP E693G (Arctic)
Modification: Plcg2: Knock-In; App: Knock-In
Disease Relevance: Alzheimer's Disease
Strain Name: B6.Cg-Plcg2^em1Msasn/J x App^tm3.1Tcs/App^tm3.1Tcs
Genetic Background: C57BL/6
Availability: Plcg2*P522R mice are available from The Jackson Laboratory, JAX Stock# 029598; APP^NL-G-F mice are available through Takaomi Saido.

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 missense 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; Olive et al., 2020; 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 a slower rate of cognitive decline and lower levels of total tau and p-tau181 in the cerebrospinal fluid of people with mild cognitive impairment (Kleineidam et al., 2020), less tau pathology in the brains of neuropathologically confirmed DLB and PSP cases (Strickland et al., 2020), and increased longevity (van der Lee et al., 2019).

The P522R variant is a mild hypermorph (i.e., the variant slightly increases the enzymatic activity of PLCγ2) (Magno et al., 2019).

CRISPR/Cas9 gene editing was used to introduce the P522R variant into the mouse Plcg2 gene. These Plcg2*P522R knock-in mice were then intercrossed with APP^NL-G-F knock-in mice, in which the mouse App gene was modified to contain a humanized Aβ region and the Swedish (“NL”), Iberian (“F”), and Arctic (“G”) mutations linked to Alzheimer’s disease (Bevan et al., 2023).

APP^NL-G-F mice homozygous for the P522R variant had increased amyloid plaque burdens and decreased microglia-plaque interactions, compared with mice carrying wild-type Plcg2. This finding contrasts with that seen in Plcg2*P522R x 5xFAD mice, where the P522R variant reduced plaque burdens and enhanced microglia-plaque interactions. Nonetheless, the P522R variant protected against synapse loss in both the APP^NL-G-F and 5xFAD models of amyloidosis.

Hereafter, mice homozygous for both the Plcg2 variant and the modified App allele are referred to as APP^NL-G-FP522R, while animals homozygous for the modified App allele without the Plcg2 mutation are referred to as APP^NL-G-F. The descriptions below refer to 6-month-old mice of both sexes, unless stated otherwise.

Plaques | Microglia | Synapse preservation | Modification Details

Plaques. Plaque burden (percent area occupied by plaques) and plaque density were greater in the hippocampi of APP^NL-G-FP522R mice, compared with APP^NL-G-F animals, regardless of sex. Plaques in the P522R carriers were also larger and more intensely stained with Thioflavin S, perhaps indicating that they were more densely compacted. Amyloid pathology in the cortex was sex- and genotype-dependent: Female APP^NL-G-F mice had higher plaque burdens and plaque densities than males, but APP^NL-G-FP522R did not show sex differences in these measures. In males, plaque burdens and plaque densities were higher in APP^NL-G-FP522R than APP^NL-G-F mice, while females did not differ by genotype. Cortical plaques were more intensely stained in APP^NL-G-FP522R than in APP^NL-G-F mice, for both sexes.

Microglia. In the hippocampus, the density of Iba1-positive microglia was higher in APP^NL-G-FP522R than APP^NL-G-F mice, regardless of sex. Compared with APP^NL-G-F mice, APP^NL-G-FP522R mice displayed reduced microglia-plaque interactions, assessed as the amount of Iba1 immunoreactivity within 30 μm of plaque cores. Levels of the lysosomal marker CD68 in peri-plaque microglia were also lower in P522R carriers.

Similar to plaques, microglial abundance in the cortex depended on sex as well as genotype. Microglial density in female APP^NL-G-F mice was higher than in males, but APP^NL-G-FP522R mice did not show sex differences. In males, cortical microglial density was higher in APP^NL-G-FP522R than APP^NL-G-F mice, while females did not differ by genotype.

Synapse preservation. The PLCγ2 R522 variant appeared to protect against synapse loss in APP^NL-G-F mice. Compared with wild-type mice, APP^NL-G-F mice had fewer puncta immunoreactive for the presynaptic marker bassoon or the postsynaptic marker PSD95 and fewer DiOlistically labeled dendritic spines, assessed in the CA1 region of the hippocampus. Levels of these synaptic indicators were largely restored in APP^NL-G-FP522R mice.

Furthermore, the PLCγ2 R522 variant had a dampening effect on microglial phagocytosis of synapses. More unengulfed synapses (represented by PSD95-immunoreactive puncta) and fewer engulfed synapses (co-localized PSD95 and CD68 immunoreactivity) were seen in peri-plaque regions in APP^NL-G-FP522R mice, compared with APP^NL-G-F mice.

Modification Details

CRISPR/Cas9 gene editing was used to introduce the P522R (c.1565 C>G ) mutation into the mouse Plcg2 gene in APOE4 Knock-In mice (JAX 027894). Correctly targeted mice were then backcrossed to C57BL/6J mice (JAX 000664) to remove the APOE4 sequence. The resulting Plcg2*R522 mice (JAX 029598) were then intercrossed with APP^NL-G-F Knock-in mice to create animals homozygous for the Plcg2 P522R mutation and the App modifications (a humanized Aβ region, and the Swedish, Iberian, and Arctic mutations linked to Alzheimer’s disease).

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. APP NL-G-F Knock-in
3. Plcg2*P522R x 5xFAD
4. APOE4 Knock-In (JAX)
5. Plcg2*P522R
6. 5xFAD (C57BL6)
7. Plcg2*P522R x 5xFAD

Paper Citations

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