Species: Mouse
Genes: Plcg2, APP, PSEN1
Mutations: APP K670_M671delinsNL (Swedish), APP I716V (Florida), APP V717I (London), PSEN1 M146L (A>C), PSEN1 L286V
Modification: Plcg2: Knock-In; APP: Transgenic; PSEN1: Transgenic
Disease Relevance: Alzheimer's Disease
Strain Name: N/A
Genetic Background: C57BL/6J
Availability: Plcg2^R522 available from The Jackson Laboratory, JAX Stock# 029598; 5xFAD available from The Jackson Laboratory, JAX MMRRC Stock# 034848.

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).

In the periphery, PLCγ2 is found on B lymphocytes, and another rare variant, M28L (rs61749044), is associated with certain lymphocytic leukemias. Analysis of data from a GWAS of >94,000 subjects (Kunkle et al., 2019; Tsai et al., 2023) showed a nominal association (p <0.05) between the M28L variant and an increased risk of Alzheimer’s disease, although this association did not meet the commonly accepted threshold for genome-wide significance (p <5×10⁻⁸). The M28L variant does not appear to affect enzymatic activity (Walliser et al., 2016), but it has been shown to reduce steady-state protein levels and thus has been regarded as a partial loss-of-function variant (Tsai et al., 2023).

Knock-in mice were generated in which the P522R or M28L mutations were introduced into the murine Plcg2 gene, and these mice were then intercrossed with 5xFAD mice, a model of aggressive amyloidosis (Tsai et al., 2023). The mice described here were homozygous for the Plcg2 variant and hemizygous for the 5xFAD transgenes—human APP and PSEN1 with a total of five AD-linked mutations.

Expression of the Plcg2 P522R variant protected against the deleterious effects of the 5xFAD transgenes on synaptic function and working memory, while reducing amyloidosis and enhancing microglia-plaque interactions. Conversely, plaque burdens were elevated, and microglia-plaque interactions attenuated, in 5xFAD^M28L mice, compared with 5xFAD mice. 5xFAD^M28L and 5xFAD mice showed similar impairments in synaptic function and cognition.

The descriptions below refer to 7.5-month-old mice of both genders, unless stated otherwise.

Levels of Plcg2 mRNA in the cortex and PLCγ2 protein levels in the cortex and spleen did not differ between 5xFAD^P522R and 5xFAD mice. However, Plcg2 mRNA levels in the cortices of 5xFAD^P522R mice were about 50 percent greater than in 5xFAD^M28L cortices, and PLCγ2 protein levels were about double.

Plaques. Plaque burdens in the cortex, assessed by high-resolution MRI, were lower in 5xFAD^P522R mice, compared with 5xFAD, as were burdens of diffuse (6E10-immunoreactive) and total (X34-positive compact plaques plus diffuse plaques) plaques in the subiculum. (5xFAD^M28L mice had higher plaque burdens than 5xFAD^P522R or 5xFAD mice.)

Microglia. The P522R mutation appeared to enhance microglial interactions with amyloid plaques, as shown by increased colocalization of the microglial marker Iba1 with 6E10-immunoreactive plaques in the subicula of 5xFAD^P522R mice, compared with 5xFAD mice. (By contrast, microglia from 5xFAD^M28L mice showed less interaction with plaques than microglia from 5xFAD animals.)

Synaptic function and plasticity. Compared with wild-type mice, 5xFAD mice exhibit impaired synaptic function, including deficits in basal synaptic transmission and long-term potentiation, lower frequencies and amplitudes of spontaneous excitatory postsynaptic currents and spontaneous inhibitory postsynaptic currents, and lower AMPA/NMDA current ratios. The PLCγ2 P522R variant protected against these synaptic deficits in 5xFAD mice: 5xFAD^P522R did not differ from wild-type mice with regard to these measures. (By contrast, 5xFAD^M28L mice displayed synaptic dysfunction like that of 5xFAD mice.)

Behavior. Compared with wild-type mice, 5xFAD mice also display behavioral deficits. As with synaptic function, the PLCγ2 P522R variant appeared to protect against cognitive impairment: Six-month-old 5xFAD^P522R mice performed similarly to wild-type mice in the Y-maze test of working memory. (5xFAD^M28L mice showed performance deficits similar to 5xFAD.)

Transcriptomics. Bulk RNA-Sequencing revealed 763 genes that were differentially expressed in the cortices of 5xFAD^P522R and 5xFAD mice. Differentially expressed genes were enriched in pathways related to lipid metabolism, inflammation and endocytosis/phagocytosis.

Further analysis—using array-based amplification-free NanoString technologies focused on genes involved in glial biology and neuropathology—revealed 579 genes differentially expressed in 5xFAD^P522R and 5xFAD cortices. Many of these genes are related to neuronal structure and connectivity and synaptic responses, consistent with a role for PLCγ2 P522R in protecting synaptic function.

Single-nuclei RNA-Seq of cortical samples depleted of neurons revealed Plcg2-genotype-dependent differences in microglial gene signatures. Microglial subtypes with transcriptome profiles associated with cell migration, endocytosis, inflammatory responses, and apoptosis were more abundant in mice carrying Plcg2 P522R.

Other. Significantly more CD8⁺ T cells were found in the brains of 5xFAD^P522R mice, compared with 5xFAD mice carrying wild-type Plcg2, and these T cells were frequently found near microglia (Claes et al., 2022). This result complements findings in a chimeric model in which human IPSC-derived microglia-like cells were transplanted into mouse brains: PLCG2 P522R microglia showed increased expression of genes involved in T-cell recruitment, compared with isogenic IPSC-derived microglia expressing wild-type PLCG2 (Claes et al., 2022). Since the murine hosts were immune-deficient, it was not possible to directly examine T-cell recruitment in this model.

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 5xFAD (JAX 034848) to create mice homozygous for the Plcg2 P522R mutation and hemizygous for the 5xFAD APP and PSEN1 transgenes.

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.

Q&A with Model Creator

Q&A with Andy Tsai.

What would you say are the unique advantages of this model? The P522R variant of PLCG2 is associated with reduced risk of AD and increased likelihood of longevity. It is one of the best models to use as a tool for drug discovery and to elucidate strategies for microglia-directed therapies. In addition, the model can be used to study the capacity of microglia to recruit T cells into the brain (Claes et al., 2022).

What do you think this model is best used for? AD and aging studies. It is also a good model to study microglial biology, the effects of peripheral immune cells on the brains, and the TREM2 pathway for drug discovery.

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References

Research Models Citations

1. 5xFAD (C57BL6)
2. Plcg2*M28L x 5xFAD
3. APOE4 Knock-In (JAX)
4. Plcg2*P522R
5. 5xFAD (C57BL6)
6. Plcg2*P522R x 5xFAD

Paper Citations

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