Different variants in the gene encoding phospholipase C-γ2—an enzyme expressed in microglia—can either raise the risk of AD, or protect against it. According to a study published September 12 in Immunity, the respective variants shape how microglia respond to Aβ plaques. Scientists led by Gary Landreth at Indiana University School of Medicine in Indianapolis report that in a mouse model of amyloidosis, microglia expressing a protective PLCγ2 variant rallied around plaques and compacted them, sparing synapses and memory loss. In mice expressing an AD risk-raising variant, microglia stalled in their transition to a neuroprotective state, mounting but a sluggish response to plaques. Overall, the findings suggest that PLCγ2 bolsters the way microglia manage amyloid.
“While mutations in PLCG2 have been extensively linked to late-onset AD risk, little is known about the in vivo functions of PLCγ2 in neurobiology or AD pathoetiology,” wrote John Lukens of the University of Virginia School of Medicine (comment below). “This study helps to bridge this gap.”
Expressed by microglia in the brain, and by various immune cells in the blood, PLCγ2 serves as a signaling hub for immune receptors, including the microglial cell-surface receptor, TREM2. Upon activation, the lipase cleaves its substrate, phospholipid phosphatidylinositol-4,5-bisphosphate (PIP2), forming diacylglycerol (DAG) and inositol-1,4,5-trisphosphate (IP3). This triggers intracellular calcium release and its numerous signaling cascades.
In 2017, scientists discovered a rare variant in the gene—P522R—that protected against AD, and later, that it protects against related diseases and even extends lifespan (Aug 2017 conference news; May 2019 news). The P522R version of PLCG2 reportedly cuts lipid substrate with more gusto than does the wild-type lipase, readying microglia to respond with great vigor when needed (Sep 2020 news).
How does PLCγ2 activity influence AD pathogenesis? To get a better idea, first author Andy Tsai and colleagues reanalyzed a genome-wide association study and sequencing data from several European-American cohorts to hunt for more PLCG2 variants (Mar 2019 news; Olive et al., 2020). In both studies, they identified a new one—M28L—that slightly elevated AD risk, although the association only reached statistical significance in the GWAS. Still, taking advantage of these opposing variants, the researchers used CRISPR to edit the protective PLCγ2-P522R or the risk-raising PLCγ2-M28L into mice. They crossed these mice onto a 5xFAD background to study how the variants influenced amyloidosis.
Relative to levels in 5xFAD mice, neither mutation changed how much PLCγ2 mRNA there was in the cortex. However, PLCγ2-M28L protein level was about half that of the wild-type, suggesting that, somehow, the M28L mutation dampened translation or stability of PLCγ2. The underlying mechanism is unknown.
The PLCγ2 variants had opposite effects on plaque load and density. While M28L boosted plaque load by 45 percent, P522R roughly halved load relative to 5xFAD controls. PLCγ2 M28L increased the proportion of diffuse plaques, while PLCγ2 P522R shifted the balance toward compact aggregates. The findings mesh with studies linking TREM2 signaling to plaque compaction, and support the notion that diffuse plaques are more toxic than their compacted counterparts (May 2016 news; Apr 2021 news).
The variants influenced microglia differently. While the risk variant hobbled their response to plaques, the protective variant rallied them to the scene. Once there, the PLCγ2-P522R-expressing microglia appeared to glom onto amyloid with more appetite than their counterparts in wild-type mice (image below).
Slack versus Mobilized. Microglia (green) surround plaques (blue) in 5xFAD mice expressing different variants of PLCG2. The M28L risk variant (middle) reduces this recruitment, while the protective P522R variant (right) ramps it up. [Courtesy of Andy Tsai.]
The findings suggested that PLCγ2 activation supports microglial containment of Aβ plaques. How so? To investigate, the scientists conducted a slew of gene-expression studies. In one, single-nuclei RNA sequencing unearthed five distinct transcriptional clusters of microglia across the control and PLC-variant 5xFAD mice. They included microglia in homeostatic, transitioning, activated A, activated B, and IFN-responsive states. Both activated clusters expressed a DAM-like profile, with the A group upregulating genes involved in endocytosis and inflammation, such as Itgax, Cd9, and Axl, and the B group ramping up expression of genes involved in apoptosis, lipid metabolism, and plaque compaction, including Lpl, ApoE, Lgals3, and Lilr4b. Relative to controls, PLCγ2-M28L mice had more microglia in the homeostatic and transitioning states, and fewer microglia in the activated states. The opposite was true for PLCγ2-P522R mice, in which more microglia had fully transitioned into the active states. The findings suggested PLCγ2 activity greases the wheels for microglial mobilization.
Ultimately, neurons reaped the benefits of stepped-up PLCγ2 activation. PLCγ2 P522R prevented memory problems, and it restored multiple measures of synaptic function to wild-type levels. Mice expressing the M28L protein fared no better on these measures, but also no worse, than controls.
Pushing Transition. Exposure to Aβ plaques triggers microglia to transition into different transcriptional states (left column). A PLCγ2 risk variant (red) thwarts, while a protective variant (blue) promotes, microglia adopting Act A and Act B states. [Courtesy of Tsai et al., Immunity, 2023.]
Tsai considers making PLCg2 more active an attractive therapeutic strategy for AD and other neurodegenerative diseases. So does Mikko Hiltunen of the University of Eastern Finland in Kuopio. Hiltunen was impressed by the rigor of the study. Previously he reported that in P522R knock-in mice, microglia had transitioned into a state of apparent readiness—expressing a mix of homeostatic and DAM signature genes—even without amyloid around. The new findings in plaque-ravaged mice confirm that the protective variant had indeed rendered the microglia more responsive, Hiltunen said.
Still, he cautioned that too much activation of PLCγ2 can be deleterious. Rare mutations that constitutively activate the lipase cause immunodeficiency and autoimmune disorders (Ombrello et al., 2012). Because TREM2 signaling activates PLCγ2, activating the receptor signaling with antibodies is another way to promote PLCγ2 signaling. Led by UEFs Mari Takalo, Hiltunen’s team is investigating how TREM2 and other immune receptors influence the protective effect of the P522R variant (Jul 2023 news).
Kathryn Monroe of Denali Therapeutics, San Francisco, discovered that PLCG2 signaling is required for the protective effects of TREM2. She said the new findings support that idea (Jun 2020 news). “However, because PLCG2 signals downstream of several immune receptors, it is possible that other signaling pathways contribute,” she added. “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,” Monroe and Joe Lewcock wrote to Alzforum. Denali’s DNL919 has recently completed a phase 1 clinical study, but has been discontinued (8 Aug press release). Other TREM2 antibodies by Alector and Vigil Neuroscience are in clinical trials. —Jessica Shugart
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.
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.
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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.
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?
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