Takalo M, Wittrahm R, Wefers B, Parhizkar S, Jokivarsi K, Kuulasmaa T, Mäkinen P, Martiskainen H, Wurst W, Xiang X, Marttinen M, Poutiainen P, Haapasalo A, Hiltunen M, Haass C. The Alzheimer's disease-associated protective Plcγ2-P522R variant promotes immune functions. Mol Neurodegener. 2020 Sep 11;15(1):52. PubMed.
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A P522R coding variant in the PLCγ2 gene was recently demonstrated to reduce the risk of Alzheimer’s disease (AD). This study by Takalo et al. is the first to examine how the P522R variant impacts microglial activity in vivo and it provides additional data to substantiate the idea that this variant acts as a mild hypermorph. Overall, it is a very interesting study that provides new insight into PLCγ2 function and how it is impacted by AD-relevant genetic variants.
The authors begin by showing that macrophages or BV2 cells expressing the P522R variant demonstrate improved survival and increased phagocytosis. They go on to examine gene expression, microglial number/morphology, and other phenotypes in homozygous P522R mice. While no changes in microglial number were observed, there was an increase in signal for F18-FEPPA, a TSPO PET tracer, in 1-year-old P522R animals suggesting an increase in activated microglia. The exact nature of this activation will require further study, though the protective effect of this variant on disease risks suggests it is likely to be beneficial rather than deleterious.
These findings are entirely consistent with the results from our recent manuscript (Andreone et al., 2020) examining the impact of PLCG2 and TREM2 activity in human iPS-derived microglia (iMG). In our work, PLCG2 or TREM2 knockout iMG demonstrate the opposite phenotypes as well as defects in lipid metabolism, while the P522R mutants displayed improved clearance of phagocytosed lipids. Taken together, these findings make a strong argument that PLCG2 signals downstream of TREM2 in microglia to regulate a range of microglial functions.
Takalo et al. also observed elevated cytokine production in cells expressing the P522R variant of PLCG2 following LPS treatment. This is perhaps not surprising as PLCG2 is known to signal downstream of a range of cell surface receptors, including TLRs, in other immune cell types. This has been a consistent finding as well, and we found that PLCG2-null iMG display reduced cytokine production. The findings from this study of P522R mutants are particularly important, as they imply that there is not something qualitatively different about the P522R mutation in PLCG2 as compared to other mutations that are known to cause inflammatory disorders. Therefore, the lack of detrimental phenotypes observed in P522R is likely a result of the mutation having less of an impact on enzymatic activity rather than impacting the TREM2 signaling axis selectively.
From a therapeutic perspective, this suggests that targeting PLCG2 directly through increasing its activity may more broadly impact microglial function than would the recently reported TREM2 agonist antibodies. Based on the results shown in this study, the effects may include increased pro-inflammatory cytokine production, but confirmation of this, as well as the impact on disease, will require further study.
References:
Andreone BJ, Przybyla L, Llapashtica C, Rana A, Davis SS, van Lengerich B, Lin K, Shi J, Mei Y, Astarita G, Di Paolo G, Sandmann T, Monroe KM, Lewcock JW. Alzheimer's-associated PLCγ2 is a signaling node required for both TREM2 function and the inflammatory response in human microglia. Nat Neurosci. 2020 Aug;23(8):927-938. Epub 2020 Jun 8 PubMed.
View all comments by Joseph LewcockWashington University in St. Louis
Washington University School of Medicine
Takalo et al. present an interesting paper on an AD-associated protective variant in PLCG2 by making a Plcγ2-P522R knock-in (KI) mouse model. The authors showed that the Plcγ2-P522R mutation increased PLCγ signaling and promoted phagocytosis, survival, and pro-inflammatory responses to lipopolysaccharide and interferon-γ in bone-marrow-derived macrophages. No obvious morphological changes were observed in KI microglia in vivo, but increased TSPO PET signal in KI microglia indicated their mild activation.
In addition, some disease-associated microglia transcripts were slightly more expressed in KI microglia versus controls, suggesting a potential beneficial effect of the P522R mutation in AD models.
This is a nice short report proving P522R as a gain-of-function mutation of PLCg and serves as a great complement to the recent paper by Andreone et al. (Andreone et al., 2020). How the mutation affects microglial functions in a neurodegenerative condition, such as AD, is yet to be determined and remains an important question to be answered.
References:
Andreone BJ, Przybyla L, Llapashtica C, Rana A, Davis SS, van Lengerich B, Lin K, Shi J, Mei Y, Astarita G, Di Paolo G, Sandmann T, Monroe KM, Lewcock JW. Alzheimer's-associated PLCγ2 is a signaling node required for both TREM2 function and the inflammatory response in human microglia. Nat Neurosci. 2020 Aug;23(8):927-938. Epub 2020 Jun 8 PubMed.
View all comments by Marco ColonnaAmsterdam University Medical Center
This is a very nice example of functional follow-up of a genetic association study finding.
I am very happy that this is taking place (it’s why we are performing the studies) and of course I am pleased it looks like the genetic association studies were right in suggesting that this is a pathway that potentially would modulate and protect for more than AD.
I do miss the investigation of the previously suggested link to the NLRP3 inflammasome.
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