Tsai AP, Dong C, Lin PB, Oblak AL, Viana Di Prisco G, Wang N, Hajicek N, Carr AJ, Lendy EK, Hahn O, Atkins M, Foltz AG, Patel J, Xu G, Moutinho M, Sondek J, Zhang Q, Mesecar AD, Liu Y, Atwood BK, Wyss-Coray T, Nho K, Bissel SJ, Lamb BT, Landreth GE. Genetic variants of phospholipase C-γ2 alter the phenotype and function of microglia and confer differential risk for Alzheimer's disease. Immunity. 2023 Sep 12;56(9):2121-2136.e6. Epub 2023 Sep 1 PubMed.

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  1. While mutations in PLCG2 have been extensively linked to late-onset AD risk in humans, little is currently known about the in vivo functions of PLCG2 in neurobiology or AD disease pathoetiology. Findings from this study help to bridge this gap in knowledge by providing novel insights into how two separate PLCG2 gene variants impact various clinically relevant aspects of microglial biology and Alzheimer’s-related disease progression. Their work is also noteworthy as they report the identification of a new PLCG2 variant (PLCG2M28L) in AD.  

    From their studies, they report that the PLCG2M28L and PLCG2P522R variants have divergent effects in the 5xFAD mouse model of AD-related amyloidosis. More specifically, they convincingly and rigorously demonstrate that the PLCG2P522R variant ameliorates disease in the 5xFAD mouse model, whereas the PLCG2M28L variant was shown to cause exacerbated disease that is characterized by increased plaque burden, aberrant microglial mobilization and activation, and defects in Aβ phagocytosis.

    Using a combination of RNA-sequencing and Nanostring techniques, they also provide compelling evidence that the PLCG2 variants elicit distinct microglial transcriptional programs in response to Aβ-mediated pathology.

    View all comments by John Lukens

  2. Tsai et al. provide further biological support for PLCG2 as an important Alzheimer’s disease modifying microglial gene by investigating the impact of a novel loss-of-function PLCG2 variant (M28L) in AD mouse models. Previous work has focused on the P522R mild gain-of-function PLCG2 variant that reduces risk for AD and other neurodegenerative diseases and increases longevity (Bellenguez et al., 2022; van der Lee et al., 2019). 

    In contrast, M28L is a putative AD risk variant (p<0.05 in Kunkle et al., 2019; however, p>0.05 in other AD genetic associations studies: Olive et al., 2020; Schwartzentruber et al., 2021; Bellenguez et al., 2022).

    This molecular lesion is positioned in the PH domain and required for plasma membrane localization of PLCγ2. Although the current genetic data supporting the relevance for the M28L variant is not as robust as that reported for P522R in AD, Tsai and colleagues generated AD mouse models carrying the PLCG2 M28L variant to evaluate its impact on AD pathology, synaptic function, and microglial state, and compared to mice expressing WT or the P522R protective variant.

    Notably, these mouse models show reduced (M28L) or increased (P522R) PLCγ2 protein expression levels in the cortex. In addition to the described functional effects of the variants, it will be important to determine whether PLCγ2 protein expression levels are altered in human variant carriers with similar directionality; this will help to understand how well the mouse models replicate the human variant molecular phenotypes.

    These new findings, together with previous studies (Takalo et al., 2020), suggest a putative allelic series for PLCG2, in which reduced activity increases AD risk and mildly enhanced activity confers neuroprotection. Through examination of the impact of each variant in the 5xFAD model, this study contributes to a better understanding of the biological effects of PLCγ2 functional impact to microglia state in a disease context, in which reduced PLCγ2 activity impairs microglial transition to responsive states, in contrast to the protective variant which leads to an increased percentage of microglia transitioning from a homeostatic to a more responsive state.

    As PLCγ2 has been shown to be required for protective effects downstream of TREM2 (Andreone et al., 2020), it is possible that the impact of PLCG2 genetic variants on microglial cell state result from alterations in signaling downstream of TREM2. In this new publication, the authors show PLCγ2-dependent effects on amyloid plaque pathology and synaptic function in opposite directions based on PLCG2 variant activity, which is consistent with this hypothesis. However, because PLCγ2 signals downstream of several different immune receptors, it is possible that other signaling pathways contribute. Either way, this data supports an exciting and novel therapeutic hypothesis to mildly agonize PLCG2 directly, based on the functional implications of the human genetic AD variants.

    Future questions remain in terms of interpreting the functional consequences of the PLCG2 human genetics, including the impact of risk and protective variants on peripheral immune responses.

    References:

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    View all comments by Joseph Lewcock

  3. Genome association studies have unequivocally linked genetic risks of late-onset Alzheimer's disease with the dysregulation of immune cells, particularly microglia. Interestingly, a number of protective alleles with selective expression in microglia have also been identified. Human PLCG2 is one such gene, the variants of which confer opposing effects on AD risk. This provides a unique window to dissect the molecular mechanisms and signaling pathways in microglia underlying AD pathogenesis.

    In this study, Tsai et al. identified an additional PLCG2 allele, M28L, associated with an increased risk for AD, and comprehensively characterized how gain- and loss-of-function PLCG2 AD variants alter the microglial transcriptome and phenotypes in mouse models of amyloidosis. They observed that the PLCG2 P522R (gain-of-function) variant reduces plaque loads, increases microglial Aβ uptake and plaque engagement, and displays higher levels of plaque-responsive microglial gene expression. This hypermorphic variant also alleviates impairments in synaptic plasticity and function, thereby improving animal behavioral performance associated with working memory. In contrast, the M28L (loss-of-function) allele displays almost the mirror opposite phenotypes, with less responsiveness of microglia to plaques and worsening functional outcomes.

    Following the recent characterization of TREM2 and Syk signaling in microglial contribution to AD, this study uncovers a crucial link connecting cell surface signals to the transcription of key effector genes, such as immune modulators and cytokines in AD. It lays a solid foundation for guiding future therapeutic design by leveraging neuroprotective microglial responses to attenuate AD pathology.

    This landmark paper also opens up numerous exciting questions that await future investigations. For example, given the distinct functions of disease-associated microglia in amyloid vs. tau models, how do these PLCG2 variants manifest their effects in tauopathy? With the pleiotropic roles of DAG, IP3, and Ca2+, what are the downstream signaling events that orchestrate the complex crosstalk between various pathways? How are these changes in microglial gene expression translated into modifications of synaptic function, neurodegeneration, and ultimately cognition?

    View all comments by Qingyun (Tristan) Li

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This paper appears in the following:

News

  1. PLCγ2 Variants Toggle Microglial Plaque Compactors

Research Models

  1. Plcg2*M28L x 5xFAD
  2. Plcg2*P522R x 5xFAD
  3. Plcg2*P522R