. A nonsynonymous mutation in PLCG2 reduces the risk of Alzheimer's disease, dementia with Lewy bodies and frontotemporal dementia, and increases the likelihood of longevity. Acta Neuropathol. 2019 May 27; PubMed.

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  1. This study represents an independent replication of the association of PLCG2 rs72824905 with Alzheimer’s disease and suggests the possibility of an association with DLB, FTD, and longevity.

    Once an association with Alzheimer's disease is established for a variant/gene it is tempting to try to also establish an association with AD-related diseases such as FTD and DLB. This is usually not as straightforward for these diseases as it is for AD for two main reasons. First, the lower prevalence of FTD and DLB in the population makes it more difficult to establish large cohorts, and consequently, have sufficiently powered studies. Smaller numbers can amplify the heterogeneity in diagnoses usually associated with these diseases. Second, the frequencies of rare variants vary greatly among populations, which can be a strong confounder in this type of study. Consequently, it is difficult to assess if the nominal associations found for DLB and FTD are real, or if they result from the absence of population stratification corrections, or if they represent residual associations, with possible AD contaminations in these cohorts

    In our own data, we don’t see an association for this variant in DLB when studying a larger cohort of neuropathologically diagnosed cases and using stringent quality-control procedures and correction for population stratification. Additionally, the diseases not showing an association with the variant are the ones with more statistical power and corrected for population stratification (PD, ALS and MS).

    A similar line of investigation was published after TREM2 p.R47H (also a rare variant) was found to associate with the risk of developing AD. However, the largest and methodologically more complete study of this variant found no consistent evidence for association with the risk of FTD, PD, or ALS (Lill et al., 2015). 

    For neurodegenerative diseases, rare variants are still, largely, an intractable topic. To fully address this, genetic ancestry needs to be taken into account when studying sufficiently large, well-characterized cohorts.

    References:

    . The role of TREM2 R47H as a risk factor for Alzheimer's disease, frontotemporal lobar degeneration, amyotrophic lateral sclerosis, and Parkinson's disease. Alzheimers Dement. 2015 Dec;11(12):1407-1416. Epub 2015 Apr 30 PubMed.

    View all comments by Rita Guerreiro
  2. In 2017, using a whole-exome microarray and genotype imputation, a large three-stage case-control study of 85,133 participants identified an Alzheimer’s Disease (AD) protective coding variant in phospholipase C γ2 (PLCG2; Pro522Arg, rs72824905), a risk variant in Abelson Interactor Protein 3 (ABI3; Ser209Phe, rs616338), as well as a new risk variant in the previously known AD susceptibility gene TREM2 (Sims et al., 2017).

    In the first follow-up study of these variants from Mayo Clinic, we investigated five different neurodegenerative diseases for their associations with these PLCG2 and ABI3 variants (Conway et al., 2018). This first follow-up study was comprised of the following: Caucasian case-control cohorts: 2,742 AD, 231 progressive supranuclear palsy (PSP), 838 Parkinson’s disease (PD), 306 dementia with Lewy bodies (DLB) and 150 multiple system atrophy (MSA) vs. 3,351 controls; and an African-American AD case-control cohort (181 AD, 331 controls). Of the Caucasian cohorts, 1479 AD and 1491 controls were non-overlapping with the prior report.

    We validated the previously reported associations in the Caucasian AD case-control cohort and observed a similar direction of effect in DLB. Using brain gene expression data we had generated in our AMP-AD study (Allen et al., 2016), we also identified microglial gene-enriched co-expression networks with significantly higher levels in the AD temporal cortex compared to control brains, and determined this co-expression network association to be driven likely by microglial cell population changes in this brain region affected by AD pathology. We concluded that these findings, while requiring replication in larger cohorts, suggested distinct effects of the microglial genes ABI3 and PLCG2 in neurodegenerative diseases that harbor significant (AD and DLB) vs. low/no Aβ pathology.

    In the most recent international collaboration led by van der Lee and colleagues, the PLCG2 rs72824905 variant was assessed for its association with seven neurodegenerative diseases and with longevity (van der Lee et al., 2019). Consistent with the prior studies, this largest replication study to date confirmed the association with AD and found an association with DLB, where the rs72824905-G conferred a protective effect. Furthermore, this study also identified association of this variant with reduced risk of frontotemporal dementia and increased likelihood of longevity.

    Collectively, these findings further strengthen the role of the microglial-enriched gene PLCG2 in AD and DLB, the neuropathologies of which can co-occur. The van der Lee study also raises an intriguing hypothesis regarding a connection between innate immunity, longevity, and protection from several neurodegenerative diseases. The precise mechanism by which this protection occurs, the influence of this variant on specific neuropathologies and the effects of genetic variation in PLCG2 in diverse populations are future topics that remain to be addressed.

    References:

    . Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease. Nat Genet. 2017 Sep;49(9):1373-1384. Epub 2017 Jul 17 PubMed.

    . ABI3 and PLCG2 missense variants as risk factors for neurodegenerative diseases in Caucasians and African Americans. Mol Neurodegener. 2018 Oct 11;13(1):53. PubMed.

    . Human whole genome genotype and transcriptome data for Alzheimer's and other neurodegenerative diseases. Sci Data. 2016 Oct 11;3:160089. PubMed.

    . A nonsynonymous mutation in PLCG2 reduces the risk of Alzheimer's disease, dementia with Lewy bodies and frontotemporal dementia, and increases the likelihood of longevity. Acta Neuropathol. 2019 May 27; PubMed.

    View all comments by Nilufer Ertekin-Taner
  3. The paper by van der Lee et al. is another in a series of genetic studies assessing the association between the rs72824905-G variant in the PLCG2 gene and neurodegenerative diseases (Conway et al., 2018; Kleineidam et al., 2018; Sims et al., 2017). The authors confirm the protective effect of this polymorphism, and extend the previous findings by describing protection against FTD and DLB, but not PD MS and ALS. Interestingly, they also associated the polymorphism with longevity.

    Phospholipase C-γ-2 is a potentially druggable target, although currently there are no good pharmacological tools to investigate its function. Thus, the new findings suggest a potential path for drug development beyond the treatment of AD, and potentially, to promote healthy aging. Understanding the biological mechanism underlying the protective effect is fundamental for designing an appropriate therapeutic approach.

    PLCγ2 is enriched in the hematopoietic system, where it has been implicated in a variety of cell-type-specific processes, such as the regulation of B cell development and maturation and collagen-dependent platelet aggregation (Wang et al., 2000). Although the peripheral immune system and its interactions with the brain could contribute as potential mediators of the protective effect, the central players in the brain are resident macrophages, particularly, microglia.

    PLCγ2 function in microglia is unexplored. Van der Lee et al., speculate a potential role in activation of the NLRP3 inflammasome, as shown for peripheral blood mononuclear cells (Chae et al., 2015). However, the functional output of the PLCγ2 pathway ultimately depends on the particular cellular context, including not only upstream immune receptors, but also cell-type specific interaction partners, complexes, and signalling networks. Therefore, extrapolating the function of PLCγ2 as studied in the peripheral immune system to microglia should be done with caution, and would need further experimental support.

    In combination with the cellular context, the type of mutation might strongly impact the resulting phenotype. As in the case of PLCG2-associated antibody deficiency and immune dysregulation (PLAID) and autoinflammatory PLAID, both mutations lead to a significant increase in PLCγ2 activity in B cell signalling, nevertheless the distal downstream functional consequences differ substantially (Koss et al., 2014). The protective variant lies within a regulatory domain of PLCγ2, as do some of the previously described activating mutations. In contrast to the strong activation described for the immune-disease variants above, the AD protective polymorphism has been shown to slightly enhance enzymatic activity in stimulated conditions, at least in heterologous cell systems (Magno et al., 2019). If this is replicated in microglia, it would suggest that a life-long subtle potentiation of the PLCγ2 pathway is required for protection. Again, it is essential to determine the specific consequences of the variant on the microglia phenotypes to understand what the activation of this pathway entails. Would the enzyme be differently wired in the signalling cascade? Would the affinity for the substrate change? How is protection mediated?

    Protein interaction network models and co-localization studies point to Trem2 as a potential receptor upstream of PLCγ2. Downstream effectors are IP3, leading to increased cytoplasmic Ca2+, and diacyl glycerol that activates PKC and the downstream NF-κB and MAPK pathways. Increase of basal intracellular calcium is critical in activation of microglia and their processes, such as proliferation, migration, ramification, phagocytosis, and release of cytokines and other effector molecules (Kettenmann et al., 2011). Whether activation of these pathways would translate to a more efficient response to insults and clearance of dead cells, pathogenic proteins, or aggregates that accumulate with aging needs to be determined. The link with Trem2 signaling and its involvement in phagocytosis, together with the finding that the protective variant is also associated with reduced tau pathology in AD patients (Kleineidam et al., 2018), suggests that a somewhat more efficient clearance mechanism might support the protective effect. This might also explain the potential protection against other neurodegenerative disorders that are associated with accumulation of toxic aggregates.

    It has been described that microglia become senescent over decades during brain aging due to chronic activation and exhaustion (Streit et al., 2014). One other possibility is that the PLCγ2 protective variant confers an advantage later in life, for example by keeping microglia cells more “healthy” and less prone to this exhaustion effect. As commented above, AD, FTD, and DLB tend to strike later than ALS and MS. This effect could also be linked to healthy aging.

    Finally, microglia are interconnected with other brain cells and the activation/potentiation of the above-mentioned signaling pathways could affect the function of neurons, astrocytes, endothelial cells via direct contact (e.g., synapse phagocytosis), as well as via production of cytokines and other mediators.

    GWAS have pointed to the immune system as a key player in AD. Moreover, the identification of protective coding variants can inform hypothesis-driven drug discovery programs. PLCγ2 and the protective variant provide such an example. However, considerable research effort is required to further characterize the function of this enzyme and the impact of the protective mutation in specific cell types associated with the disease development, as well on brain function more generally.

    Identifying specific pharmacological tool compounds (activators or inhibitors) to explore this pathway on disease-relevant cell systems would be beneficial for the field.

    References:

    . Connecting two pathways through Ca 2+ signaling: NLRP3 inflammasome activation induced by a hypermorphic PLCG2 mutation. Arthritis Rheumatol. 2015 Feb;67(2):563-7. PubMed.

    . ABI3 and PLCG2 missense variants as risk factors for neurodegenerative diseases in Caucasians and African Americans. Mol Neurodegener. 2018 Oct 11;13(1):53. PubMed.

    . Physiology of microglia. Physiol Rev. 2011 Apr;91(2):461-553. PubMed.

    . PLCG2 Protective Variant p.P522R Modulates Tau Pathology and Disease Progression in Patients with Mild Cognitive Impairment. The Lancet Preprints, December 29, 2018; posted January 2, 2019. Retrieved from https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3307649

    . Dysfunction of phospholipase Cγ in immune disorders and cancer. Trends Biochem Sci. 2014 Dec;39(12):603-11. Epub 2014 Oct 30 PubMed.

    . Alzheimer's disease phospholipase C-gamma-2 (PLCG2) protective variant is a functional hypermorph. Alzheimers Res Ther. 2019 Feb 2;11(1):16. PubMed.

    . Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease. Nat Genet. 2017 Sep;49(9):1373-1384. Epub 2017 Jul 17 PubMed.

    . Microglial pathology. Acta Neuropathol Commun. 2014 Sep 26;2(1):142. PubMed.

    . Phospholipase Cgamma2 is essential in the functions of B cell and several Fc receptors. Immunity. 2000 Jul;13(1):25-35. PubMed.

    View all comments by Lorenza Magno

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