CoChat
Sign Up
Cited by 73Neuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatmentsMultiple Sclerosis Research Studies

APOE4 confers transcriptomic and functional alterations to primary mouse microglia

Open access
Machlovi, Saima I., Neuner, Sarah M., Hemmer, Brittany M., Khan, Riana, Liu, Yiyuan, Huang, Min, Zhu, Jeffrey D., Castellano, Joseph M. +3 more·2022·Neurobiology of Disease
DOI 10.1016/j.nbd.2022.105615PMC PMC8934202
Open this paper in CoChat — free account

Abstract

Common genetic variants in more than forty loci modulate risk for Alzheimer's disease (AD). AD risk alleles are enriched within enhancers active in myeloid cells, suggesting that microglia, the brain-resident macrophages, may play a key role in the etiology of AD. A major genetic risk factor for AD is Apolipoprotein E (APOE) genotype, with the ε4/ε4 (E4) genotype increasing risk for AD by approximately 15 fold compared to the most common ε3/ε3 (E3) genotype. However, the impact of APOE genotype on microglial function has not been thoroughly investigated. To address this, we cultured primary microglia from mice in which both alleles of the mouse Apoe gene have been humanized to encode either human APOE ε3 or APOE ε4. Relative to E3 microglia, E4 microglia exhibit altered morphology, increased endolysosomal mass, increased cytokine/chemokine production, and increased lipid and lipid droplet accumulation at baseline. These changes were accompanied by decreased translation and increased phosphorylation of eIF2ɑ and eIF2ɑ-kinases that participate in the integrated stress response, suggesting that E4 genotype leads to elevated levels of cellular stress in microglia relative to E3 genotype. Using live-cell imaging and flow cytometry, we also show that E4 microglia exhibited increased phagocytic uptake of myelin and other substrates compared to E3 microglia. While transcriptomic profiling of myelin-challenged microglia revealed a largely overlapping response profile across genotypes, differential enrichment of genes in interferon signaling, extracellular matrix and translation-related pathways was identified in E4 versus E3 microglia both at baseline and following myelin challenge. Together, our results suggest E4 genotype confers several important functional alterations to microglia even prior to myelin challenge, providing insight into the molecular and cellular mechanisms by which APOE4 may increase risk for AD.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1016/j.nbd.2022.105615

Cites

47 of 47 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Primary mouse microglia expressing human E4 exhibit changes in morphology and increased cytokine production associated with LD accumulation compared to E3 microglia.

    “Machlovi et al. previously showed that primary mouse microglia expressing human E4 exhibit changes in morphology and increased cytokine production associated with LD accumulation compared to E3 microglia (Machlovi et al., 2022).”

    From APOE4 reshapes the lipid droplet proteome and modulates microglial inflammatory responses (2025) · cites this paper as Machlovi et al., 2022

  • The effects of APOE on the composition of lipid droplets themselves remain unexplored.

    “the effects of APOE on the composition of LDs themselves remains unexplored”

    From APOE4 reshapes the lipid droplet proteome and modulates microglial inflammatory responses (2025) · cites this paper as Machlovi et al., 2022

    The Results section on baseline E3 and E4 microglia reports differences in neutral-lipid levels and lipid-droplet abundance, but not the composition of the droplets themselves. A search for lipid-droplet composition found no passage stating that APOE’s effects on it remain unexplored; the absence of a composition analysis in this study does not establish that broader claim. No page numbers were available in our copy. (LLM, conf=0.72)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Part of this paper’s reference list could not be split into single entries.

Flagged first, then by citations

Research works printed but not linked: 114

  1. Abbink TEM, Wisse LE, Jaku E, Thiecke MJ, Voltolini-Gonzalez D, Fritsen H, Bobeldijk S, Ter Braak TJ, Polder E, Postma NL, Bugiani M, Struijs EA, Verheijen M, Straat N, van der Sluis S, Thomas AAM, Molenaar D, van der Knaap MS, 2019. Vanishing white matter: deregulated integrated stress response as therapy target. Ann. Clin. Transl. Neurol. 6, 1407– 1422. 31402619 PMC6689685
  2. Adomavicius T, Guaita M, Zhou Y, Jennings MD, Latif Z, Roseman AM, Pavitt GD, 2019. The structural basis of translational control by eIF2 phosphorylation. Nat. Commun. 10, 2136. 31086188 PMC6513899
  3. Advani VM, Ivanov P, 2019. Translational Control under Stress: Reshaping the Translatome. Bioessays 41, e1900009. PMC6541386 31026340
  4. Altmann A, Tian L, Henderson VW, Greicius MD, Alzheimer’s Disease Neuroimaging Initiative Investigators, 2014. Sex modifies the APOE-related risk of developing Alzheimer disease. Ann. Neurol. 75, 563– 573. 24623176 PMC4117990
  5. Alzheimer’s Association, 2021. Alzheimer’s disease facts and figures. Alzheimer’s Dement 17, 327– 406. 10.1002/alz.12328. 33756057 · DOI
  6. Andrews SJ, Fulton-Howard B, Goate A, 2020. Interpretation of risk loci from genome-wide association studies of Alzheimer’s disease. Lancet Neurol. 19, 326– 335. 31986256 PMC8176461
  7. Atagi Y, Liu C-C, Painter MM, Chen X-F, Verbeeck C, Zheng H, Li X, Rademakers R, Kang SS, Xu H, Younkin S, Das P, Fryer JD, Bu G, 2015. Apolipoprotein E Is a Ligand for Triggering Receptor Expressed on Myeloid Cells 2 (TREM2). J. Biol. Chem. 290, 26043– 26050. 26374899 PMC4646257
  8. Bachiller S, Jimenez-Ferrer I, Paulus A, Yang Y, Swanberg M, Deierborg T, Boza- Serrano A, 2018. Microglia in neurological diseases: a road map to brain-disease dependent-inflammatory response. Front. Cell. Neurosci. 12, 488. 30618635 PMC6305407
  9. Bampton ETW, Goemans CG, Niranjan D, Mizushima N, Tolkovsky AM, 2005. The dynamics of autophagy visualised in live cells: from autophagosome formation to fusion with endo/lysosomes. Autophagy 1, 23– 36. 16874023
  10. Berg S, Kutra D, Kroeger T, Straehle CN, Kausler BX, Haubold C, Schiegg M, Ales J, Beier T, Rudy M, Eren K, Cervantes JI, Xu B, Beuttenmueller F, Wolny A, Zhang C, Koethe U, Hamprecht FA, Kreshuk A, 2019. ilastik: interactive machine learning for (bio)image analysis. Nat. Methods. 10.1038/s41592-019-0582-9. 31570887 · DOI
  11. Bhat MY, Solanki HS, Advani J, Khan AA, Keshava Prasad TS, Gowda H, Thiyagarajan S, Chatterjee A, 2018. Comprehensive network map of interferon gamma signaling. J. Cell Commun. Signal. 12, 745. 30191398 PMC6235777
  12. Bolívar S, Anfossi R, Humeres C, Vivar R, Boza P, Munoz C, Pardo-Jimenez V, Olivares-Silva F, Díaz-Araya G, 2018. IFN-β plays both pro- and anti-inflammatory roles in the rat cardiac fibroblast through differential STAT protein activation. Front. Pharmacol. 9, 1368. 30555324 PMC6280699
  13. Cantuti-Castelvetri L, Fitzner D, Bosch-Queralt M, Weil M-T, Su M, Sen P, Ruhwedel T, Mitkovski M, Trendelenburg G, Lütjohann D, Mobius W, Simons M, 2018. Defective cholesterol clearance limits remyelination in the aged central nervous system. Science 359, 684– 688. 29301957
  14. Carret-Rebillat A-S, Pace C, Gourmaud S, Ravasi L, Montagne-Stora S, Longueville S, Tible M, Sudol E, Chang RC-C, Paquet C, Mouton-Liger F, Hugon J, 2015. Neuroinflammation and Aβ accumulation linked to systemic inflammation are decreased by genetic PKR down-regulation. Sci. Rep. 5, 8489. 25687824 PMC4330547
  15. Chesnokova E, Bal N, Kolosov P, 2017. Kinases of eIF2a Switch Translation of mRNA Subset during Neuronal Plasticity. Int. J. Mol. Sci. 18 10.3390/ijms18102213. PMC5666893 29065505 · DOI
  16. Chou A, Krukowski K, Jopson T, Zhu PJ, Costa-Mattioli M, Walter P, Rosi S, 2017. Inhibition of the integrated stress response reverses cognitive deficits after traumatic brain injury. Proc. Natl. Acad. Sci. U. S. A. 114, E6420–E6426. PMC5547647 28696288
  17. Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL, Pericak-Vance MA, 1993. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 261, 921– 923. 8346443
  18. Croft D, Mundo AF, Haw R, Milacic M, Weiser J, Wu G, Caudy M, Garapati P, Gillespie M, Kamdar MR, Jassal B, Jupe S, Matthews L, May B, Palatnik S, Rothfels K, Shamovsky V, Song H, Williams M, Birney E, Hermjakob H, Stein L, D’Eustachio P, 2014. The Reactome pathway knowledgebase. Nucleic Acids Res. 42, D472– D477. 24243840 PMC3965010
  19. Czaplinska B, Malarz K, Mrozek-Wilczkiewicz A, Musiol R, 2019. Acid selective pro-dye for cellular compartments. Sci. Rep. 9, 15304. 31653938 PMC6814713
  20. Damisah EC, Rai A, Grutzendler J, 2020. TREM2: Modulator of Lipid Metabolism in Microglia. Neuron. 105, 759– 761. 32135085
  21. Davis EJ, Foster TD, Thomas WE, 1994. Cellular forms and functions of brain microglia. Brain Res. Bull. 34, 73– 78. 8193937
  22. Dumitrescu L, Mayeda ER, Sharman K, Moore AM, Hohman TJ, 2019. Sex Differences in the Genetic Architecture of Alzheimer’s Disease. Curr. Genet. Med. Rep. 7, 13– 21. 31360619 PMC6662731
  23. Edgar R, Domrachev M, Lash AE, 2002. Gene Expression Omnibus: NCBI gene expression and hybridization array data repository. Nucleic Acids Res. 30, 207– 210. 11752295 PMC99122
  24. Egensperger R, Kosel S, von Eitzen U, Graeber MB, 1998. Microglial activation in¨ Alzheimer disease: Association with APOE genotype. Brain Pathol. 8, 439– 447. 9669695 PMC8098510
  25. Elder GA, Gama Sosa MA, De Gasperi R, 2010. Transgenic mouse models of Alzheimer’s disease. Mt Sinai J. Med. 77, 69– 81. 20101721 PMC2925685
  26. Emanuel R, Sergin I, Bhattacharya S, Turner J, Epelman S, Settembre C, Diwan A, Ballabio A, Razani B, 2014. Induction of lysosomal biogenesis in atherosclerotic macrophages can rescue lipid-induced lysosomal dysfunction and downstream sequelae. Arterioscler. Thromb. Vasc. Biol. 34, 1942– 1952. 25060788 PMC4140993
  27. Erbay E, Babaev VR, Mayers JR, Makowski L, Charles KN, Snitow ME, Fazio S, Wiest MM, Watkins SM, Linton MF, Hotamisligil GS, 2009. Reducing endoplasmic reticulum stress through a macrophage lipid chaperone alleviates atherosclerosis. Nat. Med. 15, 1383– 1391. 19966778 PMC2790330
  28. Feldstein AE, Werneburg NW, Li Z, Bronk SF, Gores GJ, 2006. Bax inhibition protects against free fatty acid-induced lysosomal permeabilization. Am. J. Physiol. Gastrointest. Liver Physiol. 290, G1339– G1346. 16484678 PMC3056273
  29. Fitz NF, Wolfe CM, Playso BE, Biedrzycki RJ, Lu Y, Nam KN, Lefterov I, Koldamova R, 2020. Trem2 deficiency differentially affects phenotype and transcriptome of human APOE3 and APOE4 mice. Mol. Neurodegener. 15, 41. 32703241 PMC7379780
  30. Friedberg JS, Aytan N, Cherry JD, Xia W, Standring OJ, Alvarez VE, Nicks R, Svirsky S, Meng G, Jun G, Ryu H, Au R, Stein TD, 2020. Associations between brain inflammatory profiles and human neuropathology are altered based on apolipoprotein E ε4 genotype. Sci. Rep. 10, 2924. 32076055 PMC7031423
  31. Fujimori T, Grabiec AM, Kaur M, Bell TJ, Fujino N, Cook PC, Svedberg FR, MacDonald AS, Maciewicz RA, Singh D, Hussell T, 2015. The Axl receptor tyrosine kinase is a discriminator of macrophage function in the inflamed lung. Mucosal Immunol. 8, 1021– 1030. 25603826 PMC4430298
  32. Gal-Ben-Ari S, Barrera I, Ehrlich M, Rosenblum K, 2018. PKR: A Kinase to Remember. Front. Mol. Neurosci. 11, 480. 30686999 PMC6333748
  33. Genin E, Hannequin D, Wallon D, Sleegers K, Hiltunen M, Combarros O, Bullido MJ, Engelborghs S, De Deyn P, Berr C, Pasquier F, Dubois B, Tognoni G, Fiévet N, Brouwers N, Bettens K, Arosio B, Coto E, Del Zompo M, Mateo I, Epelbaum J, Frank-Garcia A, Helisalmi S, Porcellini E, Pilotto A, Forti P, Ferri R, Scarpini E, Siciliano G, Solfrizzi V, Sorbi S, Spalletta G, Valdivieso F, Vepsälainen S, Alvarez V, Bosco P, Mancuso M, Panza F, Nacmias B, Bossù P, Hanon O, Piccardi P, Annoni G, Seripa D, Galimberti D, Licastro F, Soininen H, Dartigues J-F, Kamboh MI, Van Broeckhoven C, Lambert JC, Amouyel P, Campion D, 2011. APOE and Alzheimer disease: a major gene with semi-dominant inheritance. Mol. Psychiatry 16, 903– 907. 21556001 PMC3162068
  34. Guerreiro RJ, Gustafson DR, Hardy J, 2012. The genetic architecture of Alzheimer’s disease: beyond APP. PSENs APOE. Neurobiol. Aging 33, 437– 456. 20594621 PMC2980860
  35. Haberzettl P, Hill BG, 2013. Oxidized lipids activate autophagy in a JNK-dependent manner by stimulating the endoplasmic reticulum stress response. Redox Biol. 1, 56– 64. 24024137 PMC3757667
  36. Hanisch U-K, Kettenmann H, 2007. Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat. Neurosci. 10, 1387– 1394. 17965659
  37. Hasselmann J, Coburn MA, England W, Figueroa Velez DX, Kiani Shabestari S, Tu CH, McQuade A, Kolahdouzan M, Echeverria K, Claes C, Nakayama T, Azevedo R, Coufal NG, Han CZ, Cummings BJ, Davtyan H, Glass CK, Healy LM, Gandhi SP, Spitale RC, Blurton-Jones M, 2019. Development of a Chimeric Model to Study and Manipulate Human Microglia In Vivo. Neuron 103, 1016– 1033.e10. 31375314 PMC7138101
  38. Healy LM, Jang JH, Won S-Y, Lin YH, Touil H, Aljarallah S, Bar-Or A, Antel JP, 2017. MerTK-mediated regulation of myelin phagocytosis by macrophages generated from patients with MS. Neurol. Neuroimmunol. Neuroinflamm. 4, e402. 29379818 PMC5777663
  39. Holtzman DM, Herz J, Bu G, 2012. Apolipoprotein E and apolipoprotein E receptors: normal biology and roles in Alzheimer disease. Cold Spring Harb. Perspect. Med. 2, a006312. PMC3282491 22393530
  40. Hsu M, Dedhia M, Crusio WE, Delprato A, 2019. Sex differences in gene expression patterns associated with the APOE4 allele. F1000Res. 8, 387. 31448102 PMC6685458
  41. Hwang K-D, Bak MS, Kim SJ, Rhee S, Lee Y-S, 2017. Restoring synaptic plasticity and memory in mouse models of Alzheimer’s disease by PKR inhibition. Mol. Brain 10, 57. 29233183 PMC5727890
  42. Jaishy B, Abel ED, 2016. Lipids, lysosomes, and autophagy. J. Lipid Res. 57, 1619– 1635. 27330054 PMC5003162
  43. Jaishy B, Zhang Q, Chung HS, Riehle C, Soto J, Jenkins S, Abel P, Cowart LA, Van Eyk JE, Abel ED, 2015. Lipid-induced NOX2 activation inhibits autophagic flux by impairing lysosomal enzyme activity. J. Lipid Res. 56, 546– 561. 25529920 PMC4340303
  44. Jonsson T, Stefansson H, Steinberg S, Jonsdottir I, Jonsson PV, Snaedal J, Bjornsson S, Huttenlocher J, Levey AI, Lah JJ, Rujescu D, Hampel H, Giegling I, Andreassen OA, Engedal K, Ulstein I, Djurovic S, Ibrahim- Verbaas C, Hofman A, Ikram MA, van Duijn CM, Thorsteinsdottir U, Kong A, Stefansson K, 2013. Variant of TREM2 associated with the risk of Alzheimer’s disease. N. Engl. J. Med. 368, 107– 116. 23150908 PMC3677583
  45. Kapellos TS, Taylor L, Lee H, Cowley SA, James WS, Iqbal AJ, Greaves DR, 2016. A novel real time imaging platform to quantify macrophage phagocytosis. Biochem. Pharmacol. 116, 107– 119. 27475716 PMC5012892
  46. Kawai T, Akira S, 2011. Toll-like receptors and their crosstalk with other innate receptors in infection and immunity. Immunity 34, 637– 650. 21616434
  47. Kloske CM, Wilcock DM, 2020. The Important Interface Between Apolipoprotein E and Neuroinflammation in Alzheimer’s Disease. Front. Immunol. 11, 754. 32425941 PMC7203730
  48. Knouff C, Hinsdale ME, Mezdour H, Altenburg MK, Watanabe M, Quarfordt SH, Sullivan PM, Maeda N, 1999. Apo E structure determines VLDL clearance and atherosclerosis risk in mice. J. Clin. Invest. 103, 1579– 1586. 10359567 PMC408371
  49. Koga H, Kaushik S, Cuervo AM, 2010. Altered lipid content inhibits autophagic vesicular fusion. FASEB J. 24, 3052– 3065. 20375270 PMC2909278
  50. Konishi H, Kiyama H, 2018. Microglial TREM2/DAP12 Signaling: A Double-Edged Sword in Neural Diseases. Front. Cell. Neurosci. 12, 206. 30127720 PMC6087757
  51. Konttinen H, Cabral-da-Silva MEC, Ohtonen S, Wojciechowski S, Shakirzyanova A, Caligola S, Giugno R, Ishchenko Y, Hernandez D,´ Fazaludeen MF, Eamen S, Budia MG, Fagerlund I, Scoyni F, Korhonen P, Huber N, Haapasalo A, Hewitt AW, Vickers J, Smith GC, Oksanen M, Graff C, Kanninen KM, Lehtonen S, Propson N, Schwartz MP, Pebay A,´ Koistinaho J, Ooi L, Malm T, 2019. PSEN1ΔE9, APPswe, and APOE4 Confer Disparate Phenotypes in Human iPSC-Derived Microglia. Stem Cell Rep. 13, 669– 683. PMC6829767 31522977
  52. Kucera M, Isserlin R, Arkhangorodsky A, Bader GD, 2016. AutoAnnotate: A Cytoscape app for summarizing networks with semantic annotations. F1000Res. 5, 1717. 27830058 PMC5082607
  53. Lehmann MH, Torres-Domínguez LE, Price PJR, Brandmüller C, Kirschning CJ, Sutter G, 2016. CCL2 expression is mediated by type I IFN receptor and recruits NK and T cells to the lung during MVA infection. J. Leukoc. Biol. 99, 1057– 1064. 26992431
  54. Li K, Underhill DM, 2020. C-Type Lectin Receptors in Phagocytosis. Curr. Top. Microbiol. Immunol. 429, 1– 18. 32060644
  55. Lian H, Roy E, Zheng H, 2016. Protocol for Primary Microglial Culture Preparation. Bio Protoc. 6 10.21769/BioProtoc.1989. PMC5669279 29104890 · DOI
  56. Liao Y, Wang J, Jaehnig EJ, Shi Z, Zhang B, 2019. WebGestalt 2019: gene set analysis toolkit with revamped UIs and APIs. Nucleic Acids Res. 47, W199– W205. 31114916 PMC6602449
  57. Lillis AP, Greenlee MC, Mikhailenko I, Pizzo SV, Tenner AJ, Strickland DK, Bohlson SS, 2008. Murine low-density lipoprotein receptor-related protein 1 (LRP) is required for phagocytosis of targets bearing LRP ligands but is not required for C1q-triggered enhancement of phagocytosis. J. Immunol. 181, 364– 373. 18566402 PMC2663906
  58. Liu C-C, Liu C-C, Kanekiyo T, Xu H, Bu G, 2013. Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat. Rev. Neurol. 9, 106– 118. 23296339 PMC3726719
  59. Luzio JP, Pryor PR, Bright NA, 2007. Lysosomes: fusion and function. Nat. Rev. Mol. Cell Biol. 8, 622– 632. 17637737
  60. Ma L, Ouyang Q, Werthmann GC, Thompson HM, Morrow EM, 2017. Live-cell Microscopy and Fluorescence-based Measurement of Luminal pH in Intracellular Organelles. Front. Cell Dev. Biol. 5, 71. 28871281 PMC5566985
  61. Manser C, Stevenson A, Banner S, Davies J, Tudor EL, Ono Y, Leigh PN, McLoughlin DM, Shaw CE, Miller CCJ, 2008. Deregulation of PKN1 activity disrupts neurofilament organisation and axonal transport. FEBS Lett. 582, 2303– 2308. 18519042 PMC4516414
  62. Martina JA, Diab HI, Brady OA, Puertollano R, 2016. TFEB and TFE 3 are novel components of the integrated stress response. EMBO J. 35, 479– 495. 26813791 PMC4772850
  63. Mashud R, Nomachi A, Hayakawa A, Kubouchi K, Danno S, Hirata T, Matsuo K, Nakayama T, Satoh R, Sugiura R, Abe M, Sakimura K, Wakana S, Ohsaki H, Kamoshida S, Mukai H, 2017. Impaired lymphocyte trafficking in mice deficient in the kinase activity of PKN1. Sci. Rep. 7, 7663. 28794483 PMC5550459
  64. Mazaheri F, Breus O, Durdu S, Haas P, Wittbrodt J, Gilmour D, Peri F, 2014. Distinct roles for BAI1 and TIM-4 in the engulfment of dying neurons by microglia. Nat. Commun. 5, 4046. 24898390
  65. Mazumder B, Li X, Barik S, 2010. Translation control: a multifaceted regulator of inflammatory response. J. Immunol. 184, 3311– 3319. 20304832 PMC2860598
  66. McQuade A, Kang YJ, Hasselmann J, Jairaman A, Sotelo A, Coburn M, Shabestari SK, Chadarevian JP, Fote G, Tu CH, Danhash E, Silva J, Martinez E, Cotman C, Prieto GA, Thompson LM, Steffan JS, Smith I, Davtyan H, Cahalan M, Cho H, Blurton-Jones M, 2020. Gene expression and functional deficits underlie TREM2-knockout microglia responses in human models of Alzheimer’s disease. Nat. Commun. 11, 5370. 33097708 PMC7584603
  67. Milner R, Campbell IL, 2003. The extracellular matrix and cytokines regulate microglial integrin expression and activation. J. Immunol. 170, 3850– 3858. 12646653
  68. Mouton-Liger F, Rebillat A-S, Gourmaud S, Paquet C, Leguen A, Dumurgier J, Bernadelli P, Taupin V, Pradier L, Rooney T, Hugon J, 2015. PKR downregulation prevents neurodegeneration and β-amyloid production in a thiamine-deficient model. Cell Death Dis. 6, e1594. PMC4669750 25590804
  69. Muth C, Hartmann A, Sepulveda-Falla D, Glatzel M, Krasemann S, 2019. Phagocytosis of Apoptotic Cells Is Specifically Upregulated in ApoE4 Expressing Microglia in vitro. Front. Cell. Neurosci. 13, 181. 31130847 PMC6509203
  70. Nakamura T, Furuhashi M, Li P, Cao H, Tuncman G, Sonenberg N, Gorgun CZ, Hotamisligil GS, 2010. Double-stranded RNA-dependent protein kinase links pathogen sensing with stress and metabolic homeostasis. Cell 140, 338– 348. 20144759 PMC2820414
  71. Neher JJ, Neniskyte U, Brown GC, 2012. Primary phagocytosis of neurons by inflamed microglia: potential roles in neurodegeneration. Front. Pharmacol. 3, 27. 22403545 PMC3288722
  72. Novikova G, Kapoor M, Abud EM, Efthymiou AG, Cheng H, Fullard JF, Bendl J, Roussos P, Poon WW, Hao K, Marcora E, Goate AM, 2019. Integration of Alzheimer’s disease genetics and myeloid cell genomics identifies novel causal variants, regulatory elements, genes and pathways. Cold Spring Harbor Lab. 10.1101/694281. · DOI · Paper page
  73. Oliveira MM, Lourenco MV, Longo F, Kasica NP, Yang W, Ureta G, Ferreira DDP, Mendonça PHJ, Bernales S, Ma T, De Felice FG, Klann E, Ferreira ST, 2021. Correction of eIF2-dependent defects in brain protein synthesis, synaptic plasticity, and memory in mouse models of Alzheimer’s disease. Sci. Signal. 14 10.1126/scisignal.abc5429. PMC8317334 33531382 · DOI
  74. Olzmann JA, Carvalho P, 2019. Dynamics and functions of lipid droplets. Nat. Rev. Mol. Cell Biol. 20, 137– 155. 30523332 PMC6746329
  75. Onat UI, Yildirim AD, Tufanli O, Çimen I, Kocatürk B, Veli Z, Hamid SM, Shimada K, Chen S, Sin J, Shah PK, Gottlieb RA, Arditi M, Erbay E, 2019. Intercepting the lipid-induced integrated stress response reduces atherosclerosis. J. Am. Coll. Cardiol. 73, 1149– 1169. 30871699 PMC6424590
  76. Pakos-Zebrucka K, Koryga I, Mnich K, Ljujic M, Samali A, Gorman AM, 2016. The integrated stress response. EMBO Rep. 17, 1374– 1395. 27629041 PMC5048378
  77. Panousis CG, Zuckerman SH, 2000. Regulation of cholesterol distribution in macrophage-derived foam cells by interferon-gamma. J. Lipid Res. 41, 75– 83. 10627504
  78. Park D, Tosello-Trampont A-C, Elliott MR, Lu M, Haney LB, Ma Z, Klibanov AL, Mandell JW, Ravichandran KS, 2007. BAI1 is an engulfment receptor for apoptotic cells upstream of the ELMO/Dock180/Rac module. Nature 450, 430– 434. 17960134
  79. Patro R, Duggal G, Love MI, Irizarry RA, Kingsford C, 2017. Salmon provides fast and bias-aware quantification of transcript expression. Nat. Methods 14, 417– 419. 28263959 PMC5600148
  80. Pimenova AA, Marcora E, Goate AM, 2017. A Tale of Two Genes: Microglial Apoe and Trem2. Immunity. 47, 398– 400. 28930654
  81. Plaisier SB, Taschereau R, Wong JA, Graeber TG, 2010. Rank-rank hypergeometric overlap: identification of statistically significant overlap between gene-expression signatures. Nucleic Acids Res. 38, e169. 20660011 PMC2943622
  82. Qiu B, Simon MC, 2016. BODIPY 493/503 Staining of Neutral Lipid Droplets for Microscopy and Quantification by Flow Cytometry. Bio Protoc. 6 10.21769/BioProtoc.1912. PMC5448404 28573161 · DOI
  83. Raj T, Chibnik LB, McCabe C, Wong A, Replogle JM, Yu L, Gao S, Unverzagt FW, Stranger B, Murrell J, Barnes L, Hendrie HC, Foroud T, Krichevsky A, Bennett DA, Hall KS, Evans DA, De Jager PL, 2017. Genetic architecture of age-related cognitive decline in African Americans. Neurol. Genet. 3, e125. 28078323 PMC5206965
  84. Raport CJ, Gray PW, 2010. Chapter 24 - Chemokines and Chemokine Receptors: Structure and Function. In: Bradshaw RA, Dennis EA (Eds.), Handbook of Cell Signaling, Second edition. Academic Press, San Diego, pp. 157– 161.
  85. Rauch I, Müller M, Decker T, 2013. The regulation of inflammation by interferons and their STATs. JAKSTAT 2, e23820. PMC3670275 24058799
  86. Reiss AB, Patel CA, Rahman MM, Chan ESL, Hasneen K, Montesinos MC, Trachman JD, Cronstein BN, 2004. Interferon-gamma impedes reverse cholesterol transport and promotes foam cell transformation in THP-1 human monocytes/macrophages. Med. Sci. Monit. 10, BR420–5. 15507847
  87. Ritchie ME, Phipson B, Wu D, Hu Y, Law CW, Shi W, Smyth GK, 2015. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 43, e47. 25605792 PMC4402510
  88. Romero-Ramírez L, Nieto-Sampedro M, Barreda-Manso MA, 2017. Integrated Stress Response as a Therapeutic Target for CNS Injuries. Biomed. Res. Int. 2017, 6953156. PMC5425910 28536699
  89. Sadler AJ, Williams BRG, 2008. Interferon-inducible antiviral effectors. Nat. Rev. Immunol. 8, 559– 568. 18575461 PMC2522268
  90. Salih DA, Bayram S, Guelfi S, Reynolds RH, Shoai M, Ryten M, Brenton JW, Zhang D, Matarin M, Botia JA, Shah R, Brookes KJ, Guetta-Baranes T, Morgan K, Bellou E, Cummings DM, Escott-Price V, Hardy J, 2019. Genetic variability in response to amyloid beta deposition influences Alzheimer’s disease risk. Brain Commun. 1, fcz022. PMC7145452 32274467
  91. Sandoval-Hernandez AG, Buitrago L, Moreno H, Cardona-Gómez GP, Arboleda G,´ 2015. Role of Liver X Receptor in AD Pathophysiology. PLoS One 10, e0145467. PMC4697813 26720273
  92. Schindelin J, Arganda-Carreras I, Frise E, Kaynig V, Longair M, Pietzsch T, Preibisch S, Rueden C, Saalfeld S, Schmid B, Tinevez J-Y, White DJ, Hartenstein V, Eliceiri K, Tomancak P, Cardona A, 2012. Fiji: an open-source platform for biological-image analysis. Nat. Methods 9, 676– 682. 22743772 PMC3855844
  93. Schmidt EK, Clavarino G, Ceppi M, Pierre P, 2009. SUnSET, a nonradioactive method to monitor protein synthesis. Nat. Methods 6, 275– 277. 19305406
  94. Segev Y, Michaelson DM, Rosenblum K, 2013. ApoE ε4 is associated with eIF2α phosphorylation and impaired learning in young mice. Neurobiol. Aging 34, 863– 872. 22883908
  95. Shao S, Yang Y, Yuan G, Zhang M, Yu X, 2013. Signaling molecules involved in lipid-induced pancreatic beta-cell dysfunction. DNA Cell Biol. 32, 41– 49. 23347443 PMC3557433
  96. Shi Y, Holtzman DM, 2018. Interplay between innate immunity and Alzheimer disease: APOE and TREM2 in the spotlight. Nat. Rev. Immunol. 18, 759– 772. 30140051 PMC6425488
  97. Stewart DJ, Behrens C, Roth J, Wistuba II, 2011. Exponential decay nonlinear regression analysis of patient survival curves: preliminary assessment in non-small cell lung cancer. Lung Cancer 71, 217– 223. 20627364 PMC2962880
  98. Taniuchi S, Miyake M, Tsugawa K, Oyadomari M, Oyadomari S, 2016. Integrated stress response of vertebrates is regulated by four eIF2α kinases. Sci. Rep. 6, 32886. 27633668 PMC5025754
  99. Tcw J, Liang SA, Qian L, Pipalia NH, Chao MJ, 2019. Cholesterol and matrisome pathways dysregulated in human APOE ε4 glia. BioRxiv. preprint 713362.
  100. Tzioras M, Davies C, Newman A, Jackson R, Spires-Jones T, 2019. Invited Review: APOE at the interface of inflammation, neurodegeneration and pathological protein spread in Alzheimer’s disease. Neuropathol. Appl. Neurobiol. 45, 327– 346. 30394574 PMC6563457
  101. Ulrich JD, Burchett JM, Restivo JL, Schuler DR, Verghese PB, Mahan TE, Landreth GE, Castellano JM, Jiang H, Cirrito JR, Holtzman DM, 2013. In vivo measurement of apolipoprotein E from the brain interstitial fluid using microdialysis. Mol. Neurodegener. 8, 13. 23601557 PMC3640999
  102. Uribe-Querol E, Rosales C, 2020. Phagocytosis: Our Current Understanding of a Universal Biological Process. Front. Immunol. 11, 1066. 32582172 PMC7280488
  103. Van Giau V, Bagyinszky E, An SSA, Kim SY, 2015. Role of apolipoprotein E in neurodegenerative diseases. Neuropsychiatr. Dis. Treat. 11, 1723– 1737. 26213471 PMC4509527
  104. Villa A, Gelosa P, Castiglioni L, Cimino M, Rizzi N, Pepe G, Lolli F, Marcello E, Sironi L, Vegeto E, Maggi A, 2018. Sex-Specific Features of Microglia from Adult Mice. Cell Rep. 23, 3501– 3511. 29924994 PMC6024879
  105. Vitek MP, Brown CM, Colton CA, 2009. APOE genotype-specific differences in the innate immune response. Neurobiol. Aging 30, 1350– 1360. 18155324 PMC2782461
  106. Volmer R, van der Ploeg K, Ron D, 2013. Membrane lipid saturation activates endoplasmic reticulum unfolded protein response transducers through their transmembrane domains. Proc. Natl. Acad. Sci. U. S. A. 110, 4628– 4633. 23487760 PMC3606975
  107. White GE, Iqbal AJ, Greaves DR, 2013. CC chemokine receptors and chronic inflammation–therapeutic opportunities and pharmacological challenges. Pharmacol. Rev. 65, 47– 89. 23300131
  108. Wolfe CM, Fitz NF, Nam KN, Lefterov I, Koldamova R, 2018. The Role of APOE and TREM2 in Alzheimer’s Disease-Current Understanding and Perspectives. Int. J. Mol. Sci. 20 10.3390/ijms20010081. PMC6337314 30587772 · DOI
  109. Wong YL, LeBon L, Edalji R, Lim HB, Sun C, Sidrauski C, 2018. The small molecule ISRIB rescues the stability and activity of Vanishing White Matter Disease eIF2B mutant complexes. Elife 7. 10.7554/eLife.32733. PMC5829914 29489452 · DOI
  110. Xu Z-X, Kim GH, Tan J-W, Riso AE, Sun Y, Xu EY, Liao G-Y, Xu H, Lee SH, Do N-Y, Lee CH, Clipperton-Allen AE, Kwon S, Page DT, Lee KJ, Xu B, 2020. Elevated protein synthesis in microglia causes autism-like synaptic and behavioral aberrations. Nat. Commun. 11, 1797. 32286273 PMC7156673
  111. Zhao N, Ren Y, Yamazaki Y, Qiao W, Li F, Felton LM, Mahmoudiandehkordi S, Kueider-Paisley A, Sonoustoun B, Arnold M, Shue F, Zheng J, Attrebi ON, Martens YA, Li Z, Bastea L, Meneses AD, Chen K, Thompson JW, St John- Williams L, Tachibana M, Aikawa T, Oue H, Job L, Yamazaki A, Liu C-C, Storz P, Asmann YW, Ertekin-Taner N, Kanekiyo T, Kaddurah-Daouk R, Bu G, 2020. Alzheimer’s risk factors age, APOE genotype, and sex drive distinct molecular pathways. Neuron 106 (727– 742.e6). 32199103 PMC7388065
  112. Zhong N, Weisgraber KH, 2009. Understanding the basis for the association of apoE4 with Alzheimer’s disease: opening the door for therapeutic approaches. Curr. Alzheimer Res. 6, 415– 418. 19874264 PMC2810311
  113. Zhu PJ, Huang W, Kalikulov D, Yoo JW, Placzek AN, Stoica L, Zhou H, Bell JC, Friedlander MJ, Krnjevíc K, Noebels JL, Costa-Mattioli M, 2011. Suppression of PKR promotes network excitability and enhanced cognition by interferon-γ-mediated disinhibition. Cell 147, 1384– 1396. 22153080 PMC3569515
  114. Zyryanova AF, Kashiwagi K, Rato C, Harding HP, Crespillo-Casado A, Perera LA, Sakamoto A, Nishimoto M, Yonemochi M, Shirouzu M, Ito T, Ron D, 2021. ISRIB Blunts the Integrated Stress Response by Allosterically Antagonising the Inhibitory Effect of Phosphorylated eIF2 on eIF2B. Mol. Cell 81, 88– 103.e6. 33220178 PMC7837216

Cited by

Sorted by citations

Authors
Machlovi, S. I., Neuner, S. M., Hemmer, B. M., Khan, R., Liu, Y., Huang, M., Zhu, J. D., Castellano, J. M., Cai, D., Marcora, E., & Goate, A. M.
Affiliations
  • Icahn School of Medicine at Mount Sinai (US)
  • James J. Peters VA Medical Center (US)
Corresponding author
Goate, Alison M.
ORCID
Venue
Neurobiology of Disease
Publisher
Elsevier BV
Published
2022-03
Volume
164
Pages
105615
ISSN
0969-9961 (ISSN-L)
DOI
10.1016/j.nbd.2022.105615
PMC
PMC8934202
OpenAlex
W4205397371
Cited by
73
References
47
Citations by year
2026: 16 · 2025: 14 · 2024: 24 · 2023: 15 · 2022: 4
FWCI
4.94
Type
journal article
Language
en
Open access
Licence
Locations
  • Neurobiology of Disease (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion, cc-by-nc-nd)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Institutes of Health (1s10od026880-01, 1s10od030463-01)
  • National Institute on Aging (U01AG058635, R01AG061382, T32AG049688, R00AG051711, K99AG051711, U19AG069701)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
Keywords
APOE ε4, microglia, Alzheimer's disease risk, microglial phagocytosis, integrated stress response, eIF2α phosphorylation, lipid droplets, interferon signaling, extracellular matrix, translation (biology), transcriptome
MeSH terms
Alleles, Animals, Brain, Genotype, Neurons, Phagocytosis, Microglia, Cell Shape, Mice, Apolipoprotein E4, Transcriptome

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review