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: For Plcg2^M28L mice, contact Andy Tsai. 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, rs72824905 (P522R), is associated with a reduced risk 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) and with increased longevity (van der Lee et al., 2019). This variant has been shown to slightly increase enzymatic activity (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 M28L or P522R 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.

Like 5xFAD mice expressing wild-type Plcg2, mice expressing the M28L variant showed deficits in synaptic transmission and plasticity and impaired cognition. Plaque burdens were elevated, and microglia-plaque interactions attenuated, in 5xFAD^M28L mice, compared with 5xFAD mice. Conversely, expression of the Plcg2 P522R variant protected against the deleterious effects of the 5xFAD transgenes on synaptic function and behavior, while reducing amyloidosis and enhancing microglia-plaque interactions.

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

Similar levels of Plcg2 mRNA were found in the cortices of  5xFAD^M28L mice and 5xFAD mice homozygous for wild-type Plcg2. However, levels of PLCγ2 protein in the cortices and spleens of 5xFAD^M28L mice were about half those of 5xFAD mice. (Levels of Plcg2 mRNA and PLCγ2 protein were similar in 5xFAD^P522R and 5xFAD mice.)

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

Microglia. The M28L mutation appeared to disrupt microglial interactions with amyloid plaques. The percent area occupied by Iba1- or CLEC7A-immunoreactive microglia within X34-positive plaques was lower in 5xFAD^M28L than in 5xFAD mice. Percent colocalization of Iba1 and 6E10 immunoreactivity was also decreased in 5xFAD^M28L mice, compared with 5xFAD mice.

The number of ramified microglia expressing the homeostatic marker P2RY12 was increased in in 5xFAD^M28L mice, compared with 5xFAD and 5xFAD^P522R mice.

In addition, levels of the receptor tyrosine kinase Axl—which mediates microglial recognition and engulfment of plaques (Huang et al., 2021)—were reduced in the subicula of 5xFAD^M28L mice and increased in 5xFAD^P522R mice, compared with 5xFAD.

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. 5xFAD^M28L mice did not differ from 5xFAD with regard to these measures. (The PLCγ2 P522R variant protected against these synaptic deficits in 5xFAD mice.)

Behavior. Compared with wild-type mice, 5xFAD mice also display behavioral deficits. Six-month-old 5xFAD^M28L and 5xFAD mice showed similar deficits in working memory, assessed in the Y-maze. (The PLCγ2 P522R variant also protected against these behavioral deficits in 5xFAD mice, with 5xFAD^P522R mice performing similarly to wild-type mice.)

Transcriptomics. Bulk RNA-Sequencing revealed 47 genes that were differentially expressed in the cortices of  5xFAD^M28L and 5xFAD mice. Differentially expressed genes were enriched in pathways related to inflammation and endocytosis/phagocytosis.

Further analysis—using array-based amplification-free NanoString technologies focused on genes involved in glial biology and neuropathology—showed lower expression of several genes associated with disease-associated microglia (Itgax, Gpnmb, Ccl3, Cd74, Cybb, Lgals3, Spp1, and Lpl) in 5xFAD^M28L, compared with 5xFAD.

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 endocytosis, inflammatory responses, apoptotic processes, lipid metabolism, and plaque compaction were less abundant in 5xFAD mice carrying Plcg2 M28L.

Modification Details

Plcg2*M28L/APOE4/Trem2*R47H mice (JAX 030674)—which carry the M28L mutation in the Plcg2 gene, a humanized APOE4 sequence, and the R47H mutation knocked into Trem2—were backcrossed to C57BL/6J mice (JAX 000664) to remove the APOE4 sequence and Trem2 R47H mutation. The resulting Plcg2*M28L mice were then intercrossed with 5xFAD (JAX 034848) to create mice homozygous for the Plcg2 M28L mutation and hemizygous for the 5xFAD APP and PSEN1 transgenes.

Phenotype Characterization

Q&A with Model Creator

Q&A with Andy Tsai.

What would you say are the unique advantages of this model? The M28L variant is a loss-of-function variant of PLCG2 that can be used as a better tool to study the role of PLCG2 than the knock-out model. It is a missense mutation model that mimics the human genetics.

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.

Anything else useful or particular about this model you think our readers would like to know?  Microglia cultured from Plcg2^M28L neonatal mice (P2-P4) without the 5xFAD transgenes show decreased uptake (0.46-fold) of fluorescently-labeled Aβ42 aggregates, compared with microglia from wild-type B6 mice.

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References

Research Models Citations

1. 5xFAD (C57BL6)
2. Plcg2*P522R x 5xFAD
3. Plcg2*M28L/APOE4/Trem2*R47H

Paper Citations

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Other Citations

1. Andy Tsai

External Citations

1. JAX 030674
2. JAX 000664
3. JAX 034848
4. The Jackson Laboratory, JAX MMRRC Stock# 034848

Further Reading