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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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.
View all comments by Celeste KarchWashington 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:
Munro DA, Bestard-Cuche N, McQuaid C, Chagnot A, Shabestari SK, Chadarevian JP, Maheshwari U, Szymkowiak S, Morris K, Mohammad M, Corsinotti A, Bradford B, Mabbott N, Lennen RJ, Jansen MA, Pridans C, McColl BW, Keller A, Blurton-Jones M, Montagne A, Williams A, Priller J. Microglia protect against age-associated brain pathologies. Neuron. 2024 Aug 21;112(16):2732-2748.e8. Epub 2024 Jun 18 PubMed.
Feringa FM, Hertog SJ, Wang L, Derks RJ, Kruijff I, Erlebach L, Heijneman J, Miramontes R, Pömpner N, Blomberg N, Olivier-Jimenez D, Johansen LE, Cammack AJ, Giblin A, Toomey CE, Rose IV, Yuan H, Ward M, Isaacs AM, Kampmann M, Kronenberg-Versteeg D, Lashley T, Thompson LM, Ori A, Mohammed Y, Giera M, van der Kant R. The Neurolipid Atlas: a lipidomics resource for neurodegenerative diseases uncovers cholesterol as a regulator of astrocyte reactivity impaired by ApoE4. bioRxiv. 2024 Jul 3; PubMed.
Kogure A, Shiratori I, Wang J, Lanier LL, Arase H. PANP is a novel O-glycosylated PILRα ligand expressed in neural tissues. Biochem Biophys Res Commun. 2011 Feb 18;405(3):428-33. Epub 2011 Jan 15 PubMed.
Sun Y, Senger K, Baginski TK, Mazloom A, Chinn Y, Pantua H, Hamidzadeh K, Ramani SR, Luis E, Tom I, Sebrell A, Quinones G, Ma Y, Mukhyala K, Sai T, Ding J, Haley B, Shadnia H, Kapadia SB, Gonzalez LC, Hass PE, Zarrin AA. Evolutionarily conserved paired immunoglobulin-like receptor α (PILRα) domain mediates its interaction with diverse sialylated ligands. J Biol Chem. 2012 May 4;287(19):15837-50. Epub 2012 Mar 6 PubMed.
Rathore N, Ramani SR, Pantua H, Payandeh J, Bhangale T, Wuster A, Kapoor M, Sun Y, Kapadia SB, Gonzalez L, Zarrin AA, Goate A, Hansen DV, Behrens TW, Graham RR. Paired Immunoglobulin-like Type 2 Receptor Alpha G78R variant alters ligand binding and confers protection to Alzheimer's disease. PLoS Genet. 2018 Nov;14(11):e1007427. Epub 2018 Nov 2 PubMed.
Lopatko Lindman K, Jonsson C, Weidung B, Olsson J, Pandey JP, Prokopenko D, Tanzi RE, Hallmans G, Eriksson S, Elgh F, Lövheim H. PILRA polymorphism modifies the effect of APOE4 and GM17 on Alzheimer's disease risk. Sci Rep. 2022 Aug 2;12(1):13264. 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
Byrns CN, Perlegos AE, Miller KN, Jin Z, Carranza FR, Manchandra P, Beveridge CH, Randolph CE, Chaluvadi VS, Zhang SL, Srinivasan AR, Bennett FC, Sehgal A, Adams PD, Chopra G, Bonini NM. Senescent glia link mitochondrial dysfunction and lipid accumulation. Nature. 2024 Jun 5; PubMed.
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.
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.
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.
View all comments by Danira Toral-RiosIcahn 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.
View all comments by Edoardo MarcoraUniversity 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.
View all comments by Michael HaneyUniversity 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.
View all comments by Yajuan LiBoston 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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