Part with PILRA, Power Up Microglia?
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Ever since loss-of-function variants in the gene for PILRA, short for paired immunoglobulin-like type 2 receptor alpha, turned up as protecting against Alzheimer’s disease, scientists have wondered why. Now, a cell biology “omics” study proffers some answers.
- Loss-of-function variants in the PILRA gene protect people against AD.
- Without PILRA, microglia boost their metabolism and dampen inflammatory responses.
- An anti-PILRA antibody mimics these effects.
In a manuscript uploaded to the Research Square preprint server, researchers led by Kathryn Monroe at Denali Therapeutics, South San Francisco, and Mathew Blurton-Jones at the University of California, Irvine, report that axing the gene in microglia gives these immune cells a boost. Despite oozing with lipid droplets, which have been previously associated with disease, these PILRA-free calls flip fat metabolism in favor of antioxidant lipids, and they refrain from spewing inflammatory cytokines. Their mitochondria churn out ATP, all the while producing few reactive oxygen species, and their lysosomes readily chew up protein. In essence, the microglia seem to be fitter, if fatter, without this immunoglobulin receptor. An antibody to PILRA mimics these effects in wild-type microglia, the scientists report.
Others consider the work important. “I think this paper nicely illustrates that proper lipid turnover may have a key role in microglia and in AD,” Tony Wyss-Coray, Stanford University, California, wrote to Alzforum. His lab was the first to recognize lipid-associated microglia as dysfunctional and inflammatory in disease.
“It also illustrates that the field needs to start talking about what is in lipid droplets,” Wyss-Coray added. “Broadly speaking it seems cholesterol is good and neutral lipids, as we described, are bad. But maybe this is too simplistic.”
“This really exciting study is moving the needle in how we understand the impact of AD risk loci on cellular pathways in the brain that contribute to disease,” wrote Celeste Karch, Washington University, St. Louis (comment below).
Cells of the peripheral immune system, including neutrophils and myeloid cells, express PILRA, as do microglia in the CNS. The receptor binds a wide range of sialylated glycoproteins; however, the common G78R PILRA variant does so only weakly. This most likely explains a protective variant at the ZCWPW1/NYAP1 locus that emerged in genome-wide association studies (Bellenguez et al., 2019; Rathore et al., 2018). The two are always co-inherited.
To figure out how this loss-of-function variant might affect microglia, co-first authors Tanya Weerakkody and Hanna Sabelström at Denali knocked out the gene in human iPSC-derived microglia (iMG). Then they characterized changes to the transcriptome, metabolome, and lipidome in iMG cultures and in mice that had their own microglia replaced with the human PILRA knockout microglia. Scientists in Blurton-Jones' lab engineered these chimeric mice (Aug 2019 news).
Unlike wild-type microglia, PILRA-less iMG barely changed gene expression in response to interferon-γ or lipopolysaccharide (LPS), suggesting they tone down their response to inflammatory stimuli. In keeping with this, they released scant TNF-α, IL-6, IL-1β, and IP-10—all proinflammatory cytokines.
Their metabolome told a similar story. They produced less sphingosine, dimethylarginine, and imidazoleacetic acid than did wild-type cells, and LPS barely shifted this pattern. These metabolites modulate immune responses. On the lipidomic front, PILRA-less iMG favored antioxidant glycerophospholipids, specifically ethanolamine plasmalogens, which are reportedly depleted in AD brain, and shunned lysophosphatidylcholines, products of phospholipases activated by inflammation (Ginsberg et al., 1995; Han et al., 2001). All told, omics analyses painted a picture of less reactive microglia.
Fat and Nimble. In comparison to wild-type microglia (top), PILRA knockouts (bottom) made more lipid droplets (green) when challenged with LPS (right). They also travelled further in a chemotactic experiment (not shown). [Courtesy of Weerakkody et al., 2024.]
Knocking out PILRA induced enzymes involved in making cholesterol and its esters, which cells typically make to store this lipid. Looking into this further, the scientists found the microglia accumulated lipid droplets. Because lipid-accumulating microglia (LAMs) emerge in aging brains and around amyloid plaques, the scientists wanted to know more (Aug 2019 news). They found that, sans PILRA, microglia dialed down expression of transporters that shuttle lipids out of the cell, such as ABCA1 and ABCG1, and that they imbibed more ApoE. Increasing this further by dousing the cells with an ApoE4/cholesterol ester/high density lipoprotein mix, these cells held onto their noninflammatory state, however, suggesting that these lipid-loving microglia are better able to cope with an inflammatory pressure than cells expressing PILRA.
The authors think this helps explain why the G78R variant appears to protect against AD in APOE4 carriers only (Lopatko Lindman et al., 2022). They confirmed this by analyzing data from the Religious Orders Study/Memory and Aging Project in Chicago. Among 277 APOE4 carriers, cognition was normal in 13 percent of those with the wild-type PILRA allele. This jumped to 23 percent in people with one G78R allele, and to 37 percent in those with two copies of the loss-of-function variant. “Therefore, in an independent human cohort, we validated that increasing copies of the PILRA G78R allele exerts an AD protective effect selectively in APOE4 carriers,” the authors concluded.
In people of African descent about 10 percent carry this minor allele, while about 38 percent of Europeans do. In East Asia, it is the major allele, carried by 65 percent of that population (1000 Genomes Project Consortium: Auton et al., 2015).
There’s more. Complementing the PILRA-less iMG’s anti-inflammatory profiles, their organelle function also appeared to be reinforced. Mitochondrial respiration improved, as expression of respiratory chain components and mitochondria fusion machinery ticked up—mitochondrial fission typically indicates cell stress. These cellular powerplants made more ATP and fewer reactive oxygen species. Lysosomes more readily digested the fluorescent marker DQ-BSA than did wild-type microglia, even when the cells were treated with the ApoE/cholesterol/HDL concoction.
The cells also migrated faster toward a chemotactic agent, suggesting better motility (image below). This depended on the transcription factor STAT3. Indeed, in an unbiased look at the phosphoproteomes in wild-type and PILRA KOs, Weerakkody and colleagues found that the latter made more STAT3 and STAT1. Both help regulate inflammation and oxidative damage, while STAT3 also regulates cell migration (Debidda et al., 2005).
Lose and Move. When space frees up in cell culture, iMG lacking PILRA move to occupy it (left). They swim into a semi-permeable plate insert containing the chemoattractant C5a better than do wild-type cells. The STAT3 inhibitor SD-36 blocks this migration. [Courtesy of Weerakkody et al., 2024.]
Taking their findings in vivo, the authors used 5xFAD amyloidosis mice but replaced its microglia with human wild-type or human PILRA knockout microglia. At 6.5 months, when these chimeric mice have widespread amyloid pathology, transcriptomics analyses suggested no major difference in cell state between the two types of microglia. That said, the PILRA KOs had begun to ramp up proteins involved in mitochondrial respiration, ROS metabolism, and cell migration. The authors reported no effect on plaque burden. The data hint that a similar response occurs in vivo as in iMG in culture, and indeed in human microglia. They did not examine what happens as the mice age. Monroe told Alzforum her group is evaluating amyloid in a xenotransplant model with wild-type and PILRA KO microglia.
To learn if these findings support a therapeutic approach, the Denali scientists have developed an anti-PILRA antibody that binds both the G78 and R78 variants, but not the closely related PILRB receptor. This anti-PILRA antibody blocked a range of protein ligands from binding the PILRA immunoglobulin receptor. Treating iMG cultures with it boosted their mitochondrial respiration, tempered cytokine production, and sped migration.
The scientists plan to couple the antibody to the company’s transferrin receptor-targeting “antibody transport vehicle,” to ferry it across the blood-brain barrier. They will then test it alone, or in combination with anti-amyloid therapies for AD.—Tom Fagan
References
News Citations
- Human Microglia Make Themselves at Home in Mouse Brain
- Newly Identified Microglia Contain Lipid Droplets, Harm Brain
Mutations Citations
Paper Citations
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Further Reading
Primary Papers
- Monroe K, Weerakkody T, Sabelström H, Tatarakis D, Suh J, Chin M, Andrews S, Propson N, Balasundar S, Davis S, Yazd H, Kim DJ, Theolis R, Colmenares Y, Misker H, Parico C, Guo J, Braun D, Ha C, Raju K, Sarrafha L, Tao A, Chadarevian JP, Capocchi J, Hasselmann J, Lahian A, Tu C, Davtyan H, Lewcock J, Di Paolo G, Blurton-Jones M. PILRA regulates microglial neuroinflammation and lipid metabolism as a candidate therapeutic target for Alzheimer’s disease. Research Square, Feb 15, 2024 Research Square
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Comments
Washington University in St Louis
This really exciting study is moving the needle in how we understand the impact of AD risk loci on cellular pathways in the brain that contribute to disease.
An interesting finding from this work is the way in which PILRA may interact with APOE to impact microglia function. That PILRA impacts lipid droplets, mitochondrial function, lysosomal, and microglia function places it among an increasingly long list of AD risk genes that regulate these critical and inter-related pathways.
Washington University School of Medicine
Washington University in St. Louis
Neuroinflammation is a central feature of Alzheimer’s disease. Several factors that impinge on microglial and astrocyte function modify neurodegenerative outcome. While outright removal of microglia has been observed to be detrimental (Munro et al., 2024), other recent reports suggest that glial activation may be somewhat impaired in APOE4 carriers (Feringa et al., 2024). Thus, it is crucial to find drug targets that can modulate neuroinflammation.
The paired immunoglobulin-like type 2 receptor alpha (PILRA) binds O-glycosylated ligands (Kogure et al., 2011; Sun et al., 2012). By its role as a cellular signaling inhibitory receptor, it recruits cytoplasmic phosphatases leading to activation of ERK and STAT pathways, and it regulates inflammatory response by myeloid cell activation. PILRA is a risk gene for AD expressed by myeloid cells and other cell types in the CNS. The minor allele, rs1859788, presumably resulting in loss of function with an R78G substitution, appears to confer protection against AD risk (Rathore et al., 2018), especially in APOE4 carriers (Lopatko et al., 2022). These findings support the idea that PILRA may be a potential target for therapeutics development.
In this study, Weerakkody et al. employ CRISPR-mediated gene deletion in iPSC-derived microglia (iMG) in vitro, as well as xenotransplanted into wild-type and 5xFAD mice to show that PILRA deficiency improves inflammatory outcomes. Interestingly, PILRA loss increases APOE uptake and lipid droplet accumulation. Some recent studies have shown opposite results. For example, enhancing ApoE efflux was beneficial in a mouse model of tauopathy (Litvinchuk et al., 2024); of lipid droplets accumulated in senescent cells (Byrns et al., 2024); and lipid droplet accumulation in microglia was found to be neurotoxic (Marschallinger et al., 2020; Haney et al., 2024). Thus, it is important to fully understand how the lipid droplets in PILRA-deficient microglia differ from lipid droplets observed in other studies. It is possible that increased levels of antioxidant lipids, and reduced levels of proinflammatory lipids and metabolites in PILRA-deficient iMGs, may contribute to this difference.
It is also interesting that PILRA loss of function reduces inflammatory outcomes that may improve lysosomal efficiency to degrade proteins and impact amyloid uptake and degradation by microglia. However, in the chimeric model, plaque load, fibrillar components, and/or Aβ were not evaluated. An antibody against PILRA leads to a moderate decrease in proinflammatory cytokines produced by LPS-treated HEK293 cells. Reports of the presence of a soluble fragment of PILRA (Zhou et al., 2024) may confound the anti-PILRA drug discovery efforts.
Overall, the findings add new dimensions to our understanding of the various players controlling neuroinflammation. Studies will be required to determine the usefulness of this novel target, and the therapeutic antibody.
References:
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Zhou T, Liu J, Bao Y, Ling T, Lin C, Pan W, Zhang N, Wei Y, Xie Y, Sha Z, Li X, Wu G, Chen Q, Lu L, Jin Q, Dai Y, Wu L. Soluble PILRα: A novel plasma biomarker for atrial fibrillation progression and recurrence after catheter ablation. Clin Chim Acta. 2024 Jan 15;553:117703. Epub 2023 Dec 12 PubMed.
Icahn School of Medicine at Mount Sinai
This study on the molecular and cellular impact of PILRA loss of function (LoF) in human microglia exemplifies how to translate statistical associations between common variants and AD risk, identified by GWAS, into novel etiological and therapeutic hypotheses. Notably, from a pathobiological perspective, and as shown in our recent study of BHLHE40/41 LoF in human microglia (Podleśny-Drabiniok et al., 2024), the authors found that lipid accumulation in the form of lipid droplets and cholesterol esters does not necessarily equate to a detrimental microglial activation state, but rather the opposite.
From a therapeutic perspective, the authors were able to mimic the beneficial effects of PILRA LoF using an antagonist PILRA antibody. Moving forward, the ligand binding and immune inhibitory effects of antibody treatment should be quantitatively compared to those of the common PILRA G78R variant, which induces more than 50 percent LoF but only mildly reduces AD risk.
References:
Podleśny-Drabiniok A, Novikova G, Liu Y, Dunst J, Temizer R, Giannarelli C, Marro S, Kreslavsky T, Marcora E, Goate AM. BHLHE40/41 regulate microglia and peripheral macrophage responses associated with Alzheimer's disease and other disorders of lipid-rich tissues. Nat Commun. 2024 Mar 6;15(1):2058. PubMed.
University of Pennsylvania
In this study, Weerakkody and Sabelström et al. make a fascinating discovery in showing that PILRA KO microglia accumulate lipid droplets yet exhibit enhanced microglial function and reduced proinflammatory responses, suggestive of a protective microglial state. These results point to a possible mechanism behind the association of protection against AD in APOE4 carriers with PILRA loss-of-function variants.
One interesting element of this study is that it decouples the association of lipid-droplet-accumulating microglia (LDAM) with the proinflammatory and dysfunctional phenotypes previously established in microglia with this microglial state. Several studies have shown that LDAM are associated with proinflammatory cytokines/chemokines, increased reactive oxygen species, and decreased phagocytic, lysosomal, metabolic, and migratory function in both mouse (Marschallinger et al., 2020; Prakash et al., 2023) and human microglia (Haney et al., 2024; Victor et al., 2022; Liu et al., 2023). Reducing lipid accumulation in microglia in AD models by enhancing lipid efflux has been shown to be protective in an APOE-dependent manner (Litvinchuk et al., 2024). Furthermore, conditioned media from LDAM has been shown to be damaging to neurons (Victor et al., 2022; Haney et al., 2024).
This cell state is of particular interest in the context of Alzheimer’s disease because several studies have shown that the APOE4 genotype exacerbates lipid droplet accumulation in microglia (Haney et al., 2024; Victor et al., 2022; Liu et al., 2023), and lipid droplets form in response to amyloid (Prakash et al., 2023; Haney et al., 2024; Claes et al., 2021) and tau (Li et al., 2024) pathology.
Based on these previous studies, one would expect lipid accumulation in microglia to be accompanied by harmful, or at least dysfunctional, phenotypes. Yet in the PILRA KO background, the authors report cholesterol lipid droplet accumulation along with improved mitochondrial function, increased lysosomal degradation, enhanced migration, reduced reactive oxygen species, and reduced cytokine responses to proinflammatory stimuli. This represents a unique combination of phenotypes not previously reported in microglia.
This study opens many questions about these cellular mechanisms and consequences.
Some of the first that come to mind are:
1. Are the effects protective because of, or despite, lipid accumulation? The authors suggest that PILRA microglia might be protective because they sequester damaging lipids and lipidated APOE4 through increased APOE4 and lipid uptake and decreased lipid efflux. This could be the case, or the enhanced migratory or lysosomal function in microglia could be responsible for the AD protection associated with PILRA variants, despite lipid accumulation. A recent study suggested microglial cholesterol efflux is beneficial in AD models (Litvinchuk et al., 2024) - the opposite of the protective mechanism proposed here. It would be interesting to see if the LXR agonists, or Abca1 overexpression, used in that study to increase efflux in the PILRA KO background, reduces or enhances the potentially protective effects of the PILRA KO.
2. Does the type of lipid accumulating in microglia matter? Several studies on lipid droplets in microglia in the aging brain or AD context show triglycerides (TG) being the dominant lipids in the lipid droplets, whereas in this study, the lipids accumulating are cholesterol esters (CE). Is CE accumulation less likely to produce a dysfunctional or damaging microglial state compared to TG accumulation? Which of these lipids accumulate in microglia in human brain tissue in aging or AD? How do the lipid species accumulating in microglia differ based on disease or genotype?
3. What effect do PILRA KO microglia have on neurons, astrocytes, and AD-related pathology? Given the cellular phenotypes described in this study, one might predict these microglia to have a protective effect in the AD context, but co-culture or xenograft experiments could specifically answer this question. Also, I would like to see how these microglia interact with, or modify, pathological hallmarks of AD such as amyloid and tau. Recent studies have shown that the APOE3 Christchurch variant reduces both amyloid and tau pathology in AD mouse models (Chen et al., 2024; Nelson et al., 2023). How do the potentially protective effects of PILRA KO compare to protective APOE variants in AD models?
Overall, this very exciting study reveals a novel, potentially protective, state in microglia through knockout of a gene associated with protection against developing AD in APOE4 carriers from human genetics data.
References:
Marschallinger J, Iram T, Zardeneta M, Lee SE, Lehallier B, Haney MS, Pluvinage JV, Mathur V, Hahn O, Morgens DW, Kim J, Tevini J, Felder TK, Wolinski H, Bertozzi CR, Bassik MC, Aigner L, Wyss-Coray T. Lipid-droplet-accumulating microglia represent a dysfunctional and proinflammatory state in the aging brain. Nat Neurosci. 2020 Feb;23(2):194-208. Epub 2020 Jan 20 PubMed. Correction.
Prakash P, Manchanda P, Paouri E, Bisht K, Sharma K, Wijewardhane PR, Randolph CE, Clark MG, Fine J, Thayer EA, Crockett A, Gasmi N, Stanko S, Prayson RA, Zhang C, Davalos D, Chopra G. Amyloid β Induces Lipid Droplet-Mediated Microglial Dysfunction in Alzheimer's Disease. bioRxiv. 2023 Jun 6; PubMed.
Haney MS, Pálovics R, Munson CN, Long C, Johansson PK, Yip O, Dong W, Rawat E, West E, Schlachetzki JC, Tsai A, Guldner IH, Lamichhane BS, Smith A, Schaum N, Calcuttawala K, Shin A, Wang YH, Wang C, Koutsodendris N, Serrano GE, Beach TG, Reiman EM, Glass CK, Abu-Remaileh M, Enejder A, Huang Y, Wyss-Coray T. APOE4/4 is linked to damaging lipid droplets in Alzheimer's disease microglia. Nature. 2024 Apr;628(8006):154-161. Epub 2024 Mar 13 PubMed.
Victor MB, Leary N, Luna X, Meharena HS, Scannail AN, Bozzelli PL, Samaan G, Murdock MH, von Maydell D, Effenberger AH, Cerit O, Wen HL, Liu L, Welch G, Bonner M, Tsai LH. Lipid accumulation induced by APOE4 impairs microglial surveillance of neuronal-network activity. Cell Stem Cell. 2022 Aug 4;29(8):1197-1212.e8. PubMed.
Liu CC, Wang N, Chen Y, Inoue Y, Shue F, Ren Y, Wang M, Qiao W, Ikezu TC, Li Z, Zhao J, Martens Y, Doss SV, Rosenberg CL, Jeevaratnam S, Jia L, Raulin AC, Qi F, Zhu Y, Alnobani A, Knight J, Chen Y, Linares C, Kurti A, Fryer JD, Zhang B, Wu LJ, Kim BY, Bu G. Cell-autonomous effects of APOE4 in restricting microglial response in brain homeostasis and Alzheimer's disease. Nat Immunol. 2023 Nov;24(11):1854-1866. Epub 2023 Oct 19 PubMed.
Litvinchuk A, Suh JH, Guo JL, Lin K, Davis SS, Bien-Ly N, Tycksen E, Tabor GT, Remolina Serrano J, Manis M, Bao X, Lee C, Bosch M, Perez EJ, Yuede CM, Cashikar AG, Ulrich JD, Di Paolo G, Holtzman DM. Amelioration of Tau and ApoE4-linked glial lipid accumulation and neurodegeneration with an LXR agonist. Neuron. 2024 Feb 7;112(3):384-403.e8. Epub 2023 Nov 22 PubMed. Neuron
Claes C, Danhash EP, Hasselmann J, Chadarevian JP, Shabestari SK, England WE, Lim TE, Hidalgo JL, Spitale RC, Davtyan H, Blurton-Jones M. Plaque-associated human microglia accumulate lipid droplets in a chimeric model of Alzheimer's disease. Mol Neurodegener. 2021 Jul 23;16(1):50. PubMed.
Li Y, Munoz-Mayorga D, Nie Y, Kang N, Tao Y, Lagerwall J, Pernaci C, Curtin G, Coufal NG, Mertens J, Shi L, Chen X. Microglial lipid droplet accumulation in tauopathy brain is regulated by neuronal AMPK. Cell Metab. 2024 Jun 4;36(6):1351-1370.e8. Epub 2024 Apr 23 PubMed.
Chen Y, Song S, Parhizkar S, Lord J, Zhu Y, Strickland MR, Wang C, Park J, Tabor GT, Jiang H, Li K, Davis AA, Yuede CM, Colonna M, Ulrich JD, Holtzman DM. APOE3ch alters microglial response and suppresses Aβ-induced tau seeding and spread. Cell. 2024 Jan 18;187(2):428-445.e20. Epub 2023 Dec 11 PubMed.
Nelson MR, Liu P, Agrawal A, Yip O, Blumenfeld J, Traglia M, Kim MJ, Koutsodendris N, Rao A, Grone B, Hao Y, Yoon SY, Xu Q, De Leon S, Choenyi T, Thomas R, Lopera F, Quiroz YT, Arboleda-Velasquez JF, Reiman EM, Mahley RW, Huang Y. The APOE-R136S mutation protects against APOE4-driven Tau pathology, neurodegeneration and neuroinflammation. Nat Neurosci. 2023 Dec;26(12):2104-2121. Epub 2023 Nov 13 PubMed.
University of California, San Diego
University of California, San Diego
This study uncovers the underlying mechanism of PILRA, whose loss-of-function variant is associated with reduced risk of AD, in regulating microglia. The authors found that CRISPR-mediated PILRA KO microglia (iMg) increased ApoE uptake, lipid droplet formation, and antioxidant lipid production. Meanwhile, proinflammatory lipids and metabolites were reduced both in iPSC-derived microglia and in chimeric mice. Furthermore, a phospho-proteome profiling approach to examine WT and PILRA KO iMG lysates found that PILRA conveys its downstream effects via STAT1/3 signaling, which was validated in the human PILRA KO microglia isolated from AD chimeric mice through single-cell RNA sequencing. Finally, they identified an antagonist PILRA antibody that phenocopied PILRA LOF. This antibody has the potential to act as a therapeutic to modulate microglial immunometabolism in the setting of AD.
Most interestingly and surprisingly, despite increased lipid droplet accumulation, PILRA KO microglia seem to maintain highly efficient mitochondrial respiration, cholesterol metabolism, and lysosome function. Concurrently, they exhibit little inflammatory response and produce few reactive oxygen species. Recently, accumulating evidence in neurodegenerative diseases has pointed to microglial activation being concomitant with lipid accumulation. Such correlation is presumably due to the dysfunction of mitochondria, inefficient lipid turnover, and accumulation of toxic lipids. Yet this study suggests that accumulation of different types of lipid could have distinct impacts on microglia fitness and that they are intricately regulated by various metabolic and inflammatory signaling pathways.
STAT1/3 has been shown to regulate the redox balance and lipid metabolism in cancer cells (Totten et al., 2021; Fan et al., 2024). In addition, STAT1/3 deletion induces phenotypical switches in glial cells (Reichenbach et al., 2019; Zhao et al., 2022). This study presents another case where STAT1/3 mediates immunometabolic signaling in microglia. However, it is unclear how STAT1/3 regulates different subtypes of lipids accumulating in different systems, although lipid droplet accumulation is a common phenomenon. Other remaining questions include whether STAT1/3 has other upstream signaling inputs working synergistically to regulate microglia immunometabolism, and how they coordinate with each other.
In conclusion, this work highlights that protective LOF mutations in PILRA regulate microglia metabolism. This study spurs us to understand the mechanisms of lipid metabolic regulation of microglia and how to differentiate the “good” lipids from “bad” and their implications in AD.
References:
Totten SP, Im YK, Cepeda Cañedo E, Najyb O, Nguyen A, Hébert S, Ahn R, Lewis K, Lebeau B, La Selva R, Sabourin V, Martínez C, Savage P, Kuasne H, Avizonis D, Santos Martínez N, Chabot C, Aguilar-Mahecha A, Goulet ML, Dankner M, Witcher M, Petrecca K, Basik M, Pollak M, Topisirovic I, Lin R, Siegel PM, Kleinman CL, Park M, St-Pierre J, Ursini-Siegel J. STAT1 potentiates oxidative stress revealing a targetable vulnerability that increases phenformin efficacy in breast cancer. Nat Commun. 2021 Jun 3;12(1):3299. PubMed.
Fan Y, Zhang R, Wang C, Pan M, Geng F, Zhong Y, Su H, Kou Y, Mo X, Lefai E, Han X, Chakravarti A, Guo D. STAT3 activation of SCAP-SREBP-1 signaling upregulates fatty acid synthesis to promote tumor growth. J Biol Chem. 2024 Jun;300(6):107351. Epub 2024 May 6 PubMed.
Reichenbach N, Delekate A, Plescher M, Schmitt F, Krauss S, Blank N, Halle A, Petzold GC. Inhibition of Stat3-mediated astrogliosis ameliorates pathology in an Alzheimer's disease model. EMBO Mol Med. 2019 Feb;11(2) PubMed.
Zhao Y, Ma C, Chen C, Li S, Wang Y, Yang T, Stetler RA, Bennett MV, Dixon CE, Chen J, Shi Y. STAT1 Contributes to Microglial/Macrophage Inflammation and Neurological Dysfunction in a Mouse Model of Traumatic Brain Injury. J Neurosci. 2022 Sep 28;42(39):7466-7481. PubMed.
Boston University School of Medicine
Monroe, Blurton-Jones, and colleagues report on one of the myeloid-specific genetic targets, PILRA, that modulates AD risk. PILRA knockout microglia display lipid droplet accumulation but maintain homeostasis in an inflammatory environment by showing increased lipid-APOE uptake, enhanced mitochondria function, better chemotaxis and lysosomal proteolysis, but reduced reactive oxygen species and proinflammatory signals. The authors showed striking and interesting results especially in two respects; 1) that intracellular lipid droplet accumulation, which is usually present in glia in AD brains, may not be a detrimental phenotype and 2) that PILRA is a potential modulator for APOE4 carriers in ROSMAP data analysis.
Major AD genetic risk factors, including APOE4 and TREM2 loss of function, come with intracellular lipid droplet accumulation concurrent with disease phenotypes, such as high proinflammatory state. However, this study showed that lipids accumulating in the PILRA KO microglia comprise many protective types, without any secretion of proinflammatory cytokines. This suggests that lipid droplet accumulation could be beneficial by providing a source of energy that could improve mitochondrial function, resulting in high oxidative phosphorylation (e.g., Talari et al., 2023). Thus, characterizing lipid types associated with other organelle and cellular functions is a significant factor to consider when discussing disease mechanisms.
The authors mentioned that the NYAP1/ZCWPW1 locus in chromosome 7 is in linkage disequilibrium with the PILRA variant. In our myeloid genetic study to identify candidate causal genes through both Hi–C and SMR approaches, we showed that PILRA is indeed the gene in this locus, and that increased PILRA gene expression associated with increased risk for AD (Novikova et al., 2021). Thus, the authors‘ knockout of PILRA in this functional study validates a functional genomics finding, and it demonstrates microglia specific and protective effects for AD.
Additionally, since the PILRA receptor is only expressed in myeloid cells, targeting these particular cell types, and their receptors, or receptor signaling pathways, could offer an avenue into AD therapeutics. It would be interesting to investigate if PILRA modulation could reverse microglial function dampened by APOE4 or TMEM2 KO.
References:
Talari NK, Mattam U, Meher NK, Paripati AK, Mahadev K, Krishnamoorthy T, Sepuri NB. Lipid-droplet associated mitochondria promote fatty-acid oxidation through a distinct bioenergetic pattern in male Wistar rats. Nat Commun. 2023 Feb 11;14(1):766. PubMed.
Novikova G, Kapoor M, Tcw J, Abud EM, Efthymiou AG, Chen SX, Cheng H, Fullard JF, Bendl J, Liu Y, Roussos P, Björkegren JL, Liu Y, Poon WW, Hao K, Marcora E, Goate AM. Integration of Alzheimer's disease genetics and myeloid genomics identifies disease risk regulatory elements and genes. Nat Commun. 2021 Mar 12;12(1):1610. PubMed.
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