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Cited by 120Neuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatmentsMitochondrial Function and Pathology

Mitochondrial Regulation of Microglial Immunometabolism in Alzheimer’s Disease

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Fairley, Lauren H., Wong, Jia Hui, Barron, Anna M.·2021·Frontiers in Immunology
DOI 10.3389/fimmu.2021.624538PMC PMC7947196
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Abstract

Alzheimer’s disease (AD) is an age-associated terminal neurodegenerative disease with no effective treatments. Dysfunction of innate immunity is implicated in the pathogenesis of AD, with genetic studies supporting a causative role in the disease. Microglia, the effector cells of innate immunity in the brain, are highly plastic and perform a diverse range of specialist functions in AD, including phagocytosing and removing toxic aggregates of beta amyloid and tau that drive neurodegeneration. These immune functions require high energy demand, which is regulated by mitochondria. Reflecting this, microglia have been shown to be highly metabolically flexible, reprogramming their mitochondrial function upon inflammatory activation to meet their energy demands. However, AD-associated genetic risk factors and pathology impair microglial metabolic programming, and metabolic derailment has been shown to cause innate immune dysfunction in AD. These findings suggest that immunity and metabolic function are intricately linked processes, and targeting microglial metabolism offers a window of opportunity for therapeutic treatment of AD. Here, we review evidence for the role of metabolic programming in inflammatory functions in AD, and discuss mitochondrial-targeted immunotherapeutics for treatment of the disease.

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  • Under energy-demanding conditions, FAs are released from LDs, transported to mitochondria, and used to fuel mitochondrial oxidative phosphorylation via FAO.

    “Under energy-demanding conditions, FAs are released from their main intracellular lipid storage units, known as LDs, which mainly contain triglycerides and cholesterol esters. Free FAs are then transported to mitochondria, where they are used to fuel mitochondrial oxidative phosphorylation in a process called FA β-oxidation (FAO) [58].”

    From The protective PLCγ2-P522R variant mitigates Alzheimer’s disease-associated pathologies by enhancing beneficial microglial functions (2025) · cites this paper as [58]

  • Microglia rely on the flexible use of diverse energy sources, including FAs, to perform numerous immune functions efficiently and to maintain tissue homeostasis.

    “Microglia rely on the flexible use of diverse energy sources, including FAs, to perform numerous immune functions efficiently and to maintain tissue homeostasis [58].”

    From The protective PLCγ2-P522R variant mitigates Alzheimer’s disease-associated pathologies by enhancing beneficial microglial functions (2025) · cites this paper as [58]

  • In the AD brain, chronic and Aβ-induced inflammation promotes a sustained metabolic shift from mitochondrial oxidative phosphorylation to glycolysis, resulting in excessive lipid droplet formation and accumulation within microglia.

    “Thus, in the AD brain, chronic and Aβ-induced inflammation could promote a sustained metabolic shift from mitochondrial oxidative phosphorylation to glycolysis (44), resulting in the excessive formation and accumulation of LDs within microglia.”

    From Reducing microglial lipid load enhances β amyloid phagocytosis in an Alzheimer’s disease mouse model (2025) · cites this paper as [44]

  • There are several hypermorphic variants in PLCG2 that have been associated with autoimmune disease and cancer.

    “There are several hypermorphic variants in PLCG2 that have been associated with autoimmune disease and cancer [58–61, 66].”

    From The protective PLCγ2-P522R variant mitigates Alzheimer’s disease-associated pathologies by enhancing beneficial microglial functions (2025) · cites this paper as [58]

    The AD Genetic Risk Factors and Microglial Metabolism section discusses ApoE4 and TREM2 variants, not PLCG2 variants. Searches for PLCG2 hypermorphic variants and gain-of-function variants associated with autoimmunity or cancer found no passage addressing the claim in our copy. (LLM, conf=0.72)

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  1. [3]Johnson ECB Dammer EB Duong DM Ping L Zhou M Yin L. Large-scale proteomic analysis of Alzheimer’s disease brain and cerebrospinal fluid reveals early changes in energy metabolism associated with microglia and astrocyte activation. Nat Med (2020) 26(5): 769–80. 10.1038/s41591-020-0815-6 PMC7405761 32284590 · DOI · Paper page
  2. [5]Guerreiro R Hardy J. Genetics of Alzheimer’s disease. Neurotherapeutics (2014) 11(4): 732–7. 10.1007/s13311-014-0295-9 PMC4362699 25113539 · DOI
  3. [6]Jonsson T Stefansson H Steinberg S Jonsdottir I Jonsson PV Snaedal J. Variant of TREM2 associated with the risk of Alzheimer’s disease. N Engl J Med (2013) 368(2): 107–16. 10.1056/NEJMoa1211103 PMC3677583 23150908 · DOI · Paper page
  4. [8]Tanzi RE. The genetics of Alzheimer disease. Cold Spring Harb Perspect Med (2012) 2(10): 1– 10. 10.1101/cshperspect.a006296 PMC3475404 23028126 · DOI · Paper page
  5. [11]Angajala A Lim S Phillips JB Kim J-H Yates C You Z. Diverse Roles of Mitochondria in Immune Responses: Novel Insights Into Immuno-Metabolism. Front Immunol (2018) 9: 1605. 10.3389/fimmu.2018.01605 30050539 PMC6052888 · DOI
  6. [12]Lauro C Limatola C. Metabolic Reprograming of Microglia in the Regulation of the Innate Inflammatory Response. Front Immunol (2020) 11(493): 1– 8. 10.3389/fimmu.2020.00493 32265936 PMC7099404 · DOI · Paper page
  7. [15]Hsieh CL Koike M Spusta SC Niemi EC Yenari M Nakamura MC. A role for TREM2 ligands in the phagocytosis of apoptotic neuronal cells by microglia. J Neurochem (2009) 109(4): 1144–56. 10.1111/j.1471-4159.2009.06042.x PMC3087597 19302484 · DOI · Paper page
  8. [17]Sampaio TB Savall AS Gutierrez MEZ Pinton S. Neurotrophic factors in Alzheimer’s and Parkinson’s diseases: implications for pathogenesis and therapy. Neural Regen Res (2017) 12(4): 549. 10.4103/1673-5374.205084 28553325 PMC5436343 · DOI
  9. [18]Parkhurst CN Yang G Ninan I Savas JN Yates JR II Lafaille JJ. Microglia promote learning-dependent synapse formation through brain-derived neurotrophic factor. Cell (2013) 155(7): 1596–609. 10.1016/j.cell.2013.11.030 PMC4033691 24360280 · DOI · Paper page
  10. [19]Rajendran L Paolicelli RC. Microglia-mediated synapse loss in Alzheimer’s disease. J Neurosci (2018) 38(12): 2911–9. 10.1523/JNEUROSCI.1136-17.2017 PMC6596066 29563239 · DOI · Paper page
  11. [20]Suh H-S Zhao M-L Derico L Choi N Lee SC. Insulin-like growth factor 1 and 2 (IGF1, IGF2) expression in human microglia: differential regulation by inflammatory mediators. J Neuroinflamm (2013) 10(1): 805. 10.1186/1742-2094-10-37 PMC3607995 23497056 · DOI · Paper page
  12. [21]Asai H Ikezu S Tsunoda S Medalla M Luebke J Haydar T. Depletion of microglia and inhibition of exosome synthesis halt tau propagation. Nat Neurosci (2015) 18(11): 1584. 10.1038/nn.413 26436904 PMC4694577 · DOI
  13. [22]Bhaskar K Maphis N Xu G Varvel NH Kokiko-Cochran ON Weick JP. Microglial derived tumor necrosis factor-alpha drives Alzheimer’s disease-related neuronal cell cycle events. Neurobiol Dis (2014) 62: 273–85. 10.1016/j.nbd.2013.10.007 PMC3877710 24141019 · DOI
  14. [23]Wilkinson BL Landreth GE. The microglial NADPH oxidase complex as a source of oxidative stress in Alzheimer’s disease. J Neuroinflamm (2006) 3: 30. 10.1186/1742-2094-3-30 PMC1637099 17094809 · DOI
  15. [28]Li Q Barres BA. Microglia and macrophages in brain homeostasis and disease. Nat Rev Immunol (2018) 18(4): 225–42. 10.1038/nri.2017.125 29151590 · DOI · Paper page
  16. [30]Aryaman J Johnston IG Jones NS. Mitochondrial Heterogeneity. Front Genet (2019) 9: 718. 10.3389/fgene.2018.00718 30740126 PMC6355694 · DOI
  17. [33]Hayashi Y Yoshida M Yamato M Ide T Wu Z Ochi-Shindou M. Reverse of age-dependent memory impairment and mitochondrial DNA damage in microglia by an overexpression of human mitochondrial transcription factor a in mice. J Neurosci (2008) 28(34): 8624–34. 10.1523/jneurosci.1957-08.2008 PMC6671051 18716221 · DOI
  18. [34]Ryu JK Nagai A Kim J Lee MC McLarnon JG Kim SU. Microglial activation and cell death induced by the mitochondrial toxin 3-nitropropionic acid: in vitro and in vivo studies. Neurobiol Dis (2003) 12(2): 121–32. 10.1016/s0969-9961(03)00002-0 12667467 · DOI
  19. [35]Baik SH Kang S Lee W Choi H Chung S Kim J. A breakdown in metabolic reprogramming causes microglia dysfunction in Alzheimer’s disease. Cell Metab (2019) 30(3): 493– 507.e6. 10.1016/j.cmet.2019.06.005 31257151 · DOI · Paper page
  20. [36]Rangaraju S Dammer EB Raza SA Gao T Xiao H Betarbet R. Quantitative proteomics of acutely-isolated mouse microglia identifies novel immune Alzheimer’s disease-related proteins. Mol Neurodegener (2018) 13(1): 34. 10.1186/s13024-018-0266-4 29954413 PMC6025801 · DOI
  21. [37]Backes H Walberer M Ladwig A Rueger MA Neumaier B Endepols H. Glucose consumption of inflammatory cells masks metabolic deficits in the brain. NeuroImage (2016) 128: 54– 62. 10.1016/j.neuroimage.2015.12.044 26747749 PMC4767221 · DOI
  22. [38]Kalsbeek MJ Mulder L Yi C-X. Microglia energy metabolism in metabolic disorder. Mol Cell Endocrinol (2016) 438: 27– 35. 10.1016/j.mce.2016.09.028 27687525 · DOI
  23. [39]Sasaki A Yamaguchi H Horikoshi Y Tanaka G Nakazato Y. Expression of glucose transporter 5 by microglia in human gliomas. Neuropathol Appl Neurobiol (2004) 30(5): 447–55. 10.1111/j.1365-2990.2004.00556.x 15488021 · DOI
  24. [40]Wang L Pavlou S Du X Bhuckory M Xu H Chen M. Glucose transporter 1 critically controls microglial activation through facilitating glycolysis. Mol Neurodegener (2019) 14(1): 2. 10.1186/s13024-019-0305-9 30634998 PMC6329071 · DOI
  25. [41]Ghosh S Castillo E Frias ES Swanson RA. Bioenergetic regulation of microglia. Glia (2018) 66(6): 1200–12. 10.1002/glia.23271 PMC5903989 29219210 · DOI
  26. [43]Holland R McIntosh AL Finucane OM Mela V Rubio-Araiz A Timmons G. Inflammatory microglia are glycolytic and iron retentive and typify the microglia in APP/PS1 mice. Brain Behav Immun (2018) 68: 183–96. 10.1016/j.bbi.2017.10.017 29061364 · DOI
  27. [44]Nair S Sobotka KS Joshi P Gressens P Fleiss B Thornton C. Lipopolysaccharide-induced alteration of mitochondrial morphology induces a metabolic shift in microglia modulating the inflammatory response in vitro and in vivo. Glia (2019) 67(6): 1047–61. 10.1002/glia.23587 30637805 · DOI
  28. [45]Voloboueva LA Emery JF Sun X Giffard RG. Inflammatory response of microglial BV-2 cells includes a glycolytic shift and is modulated by mitochondrial glucose-regulated protein 75/mortalin. FEBS Lett (2013) 587(6): 756–62. 10.1016/j.febslet.2013.01.067 PMC3603371 23395614 · DOI
  29. [47]Gimeno-Bayón J López-López A Rodríguez M Mahy N. Glucose pathways adaptation supports acquisition of activated microglia phenotype. J Neurosci Res (2014) 92(6): 723–31. 10.1002/jnr.23356 24510633 · DOI
  30. [48]Mauerer R Ebert S Langmann T. High glucose, unsaturated and saturated fatty acids differentially regulate expression of ATP-binding cassette transporters ABCA1 and ABCG1 in human macrophages. Exp Mol Med (2009) 41(2): 126–32. 10.3858/emm.2009.41.2.015 PMC2679329 19287193 · DOI
  31. [49]Chandak PG Radovic B Aflaki E Kolb D Buchebner M Frohlich E. Efficient phagocytosis requires triacylglycerol hydrolysis by adipose triglyceride lipase. J Biol Chem (2010) 285(26): 20192–201. 10.1074/jbc.M110.107854 PMC2888432 20424161 · DOI · Paper page
  32. [50]Yin B Loike JD Kako Y Weinstock PH Breslow JL Silverstein SC. Lipoprotein lipase regulates Fc receptor-mediated phagocytosis by macrophages maintained in glucose-deficient medium. J Clin Invest (1997) 100(3): 649–57. 10.1172/JCI119576 PMC508233 9239412 · DOI
  33. [51]Moreira TJ Pierre K Maekawa F Repond C Cebere A Liljequist S. Enhanced cerebral expression of MCT1 and MCT2 in a rat ischemia model occurs in activated microglial cells. J Cereb Blood Flow Metab (2009) 29(7): 1273–83. 10.1038/jcbfm.2009.50 19401710 · DOI
  34. [52]Bernier L-P York EM Kamyabi A Choi HB Weilinger NL MacVicar BA. Microglial metabolic flexibility supports immune surveillance of the brain parenchyma. Nat Commun (2020) 11(1): 1– 17. 10.1038/s41467-020-15267-z 32214088 PMC7096448 · DOI
  35. [53]Barron AM Tokunaga M Zhang MR Ji B Suhara T Higuchi M. Assessment of neuroinflammation in a mouse model of obesity and beta-amyloidosis using PET. J Neuroinflamm (2016) 13(1): 221. 10.1186/s12974-016-0700-x PMC5006247 27578213 · DOI
  36. [54]Tsukada H Nishiyama S Fukumoto D Kanazawa M Harada N. Novel PET probes 18F-BCPP-EF and 18F-BCPP-BF for mitochondrial complex I: a PET study in comparison with 18F-BMS-747158-02 in rat brain. J Nucl Med (2014) 55(3): 473–80. 10.2967/jnumed.113.125328 24470629 · DOI
  37. [55]Vaishnavi SN Vlassenko AG Rundle MM Snyder AZ Mintun MA Raichle ME. Regional aerobic glycolysis in the human brain. Proc Natl Acad Sci U S A (2010) 107(41): 17757–62. 10.1073/pnas.1010459107 PMC2955101 20837536 · DOI · Paper page
  38. [57]Barron AM Ji B Fujinaga M Zhang M-R Suhara T Sahara N. In vivo positron emission tomography imaging of mitochondrial abnormalities in a mouse model of tauopathy. Neurobiol Aging (2020) 94: 140–8. 10.1016/j.neurobiolaging.2020.05.003 32623260 · DOI
  39. [58]Joshi AU Minhas PS Liddelow SA Haileselassie B Andreasson KI Dorn G 2nd. Fragmented mitochondria released from microglia trigger A1 astrocytic response and propagate inflammatory neurodegeneration. Nat Neurosci (2019) 22(10): 1635–48. 10.1038/s41593-019-0486-0 PMC6764589 31551592 · DOI · Paper page
  40. [59]McIntosh A Mela V Harty C Minogue AM Costello DA Kerskens C. Iron accumulation in microglia triggers a cascade of events that leads to altered metabolism and compromised function in APP/PS1 mice. Brain Pathol (2019) 29(5): 606–21. 10.1111/bpa.12704 PMC8028264 30661261 · DOI
  41. [60]Atlante A Amadoro G Bobba A de Bari L Corsetti V Pappalardo G. A peptide containing residues 26-44 of tau protein impairs mitochondrial oxidative phosphorylation acting at the level of the adenine nucleotide translocator. Biochim Biophys Acta (2008) 1777(10): 1289–300. 10.1016/j.bbabio.2008.07.004 18725189 · DOI
  42. [61]Rhein V Song X Wiesner A Ittner LM Baysang G Meier F. Amyloid-beta and tau synergistically impair the oxidative phosphorylation system in triple transgenic Alzheimer’s disease mice. Proc Natl Acad Sci U S A (2009) 106(47): 20057–62. 10.1073/pnas.0905529106 PMC2774257 19897719 · DOI · Paper page
  43. [62]Cenini G Rüb C Bruderek M Voos W. Amyloid β-peptides interfere with mitochondrial preprotein import competence by a coaggregation process. Mol Biol Cell (2016) 27(21): 3257–72. 10.1091/mbc.E16-05-0313 PMC5170859 27630262 · DOI
  44. [63]Mamada N Tanokashira D Ishii K Tamaoka A Araki W. Mitochondria are devoid of amyloid β-protein (Aβ)-producing secretases: Evidence for unlikely occurrence within mitochondria of Aβ generation from amyloid precursor protein. Biochem Biophys Res Commun (2017) 486(2): 321–8. 10.1016/j.bbrc.2017.03.035 28302486 · DOI
  45. [64]Schaefer PM von Einem B Walther P Calzia E von Arnim CA. Metabolic Characterization of Intact Cells Reveals Intracellular Amyloid Beta but Not Its Precursor Protein to Reduce Mitochondrial Respiration. PLoS One (2016) 11(12): e0168157. 10.1371/journal.pone.0168157 28005987 PMC5178995 · DOI
  46. [65]Aleardi A Benard G Augereau O Malgat M Talbot J Mazat J. Gradual alteration of mitochondrial structure and function by β-amyloids: importance of membrane viscosity changes, energy deprivation, reactive oxygen species production, and cytochrome c release. J Bioenerg Biomembr (2005) 37(4): 207–25. 10.1007/s10863-005-6631-3 16167177 · DOI
  47. [66]Manczak M Anekonda TS Henson E Park BS Quinn J Reddy PH. Mitochondria are a direct site of A beta accumulation in Alzheimer’s disease neurons: implications for free radical generation and oxidative damage in disease progression. Hum Mol Genet (2006) 15(9): 1437–49. 10.1093/hmg/ddl066 16551656 · DOI · Paper page
  48. [67]Petersen CAH Alikhani N Behbahani H Wiehager B Pavlov PF Alafuzoff I. The amyloid β-peptide is imported into mitochondria via the TOM import machinery and localized to mitochondrial cristae. Proc Natl Acad Sci (2008) 105(35): 13145–50. 10.1073/pnas.0806192105 PMC2527349 18757748 · DOI · Paper page
  49. [68]Du H Guo L Fang F Chen D Sosunov AA McKhann GM. Cyclophilin D deficiency attenuates mitochondrial and neuronal perturbation and ameliorates learning and memory in Alzheimer’s disease. Nat Med (2008) 14(10): 1097–105. 10.1038/nm.1868 PMC2789841 18806802 · DOI
  50. [69]Lustbader JW Cirilli M Lin C Xu HW Takuma K Wang N. ABAD directly links Abeta to mitochondrial toxicity in Alzheimer’s disease. Science (2004) 304(5669): 448–52. 10.1126/science.1091230 15087549 · DOI · Paper page
  51. [70]Manczak M Calkins MJ Reddy PH. Impaired mitochondrial dynamics and abnormal interaction of amyloid beta with mitochondrial protein Drp1 in neurons from patients with Alzheimer’s disease: implications for neuronal damage. Hum Mol Genet (2011) 20(13): 2495–509. 10.1093/hmg/ddr139 PMC3109997 21459773 · DOI
  52. [71]Chiozzi P Sarti AC Sanz JM Giuliani AL Adinolfi E Vultaggio-Poma V. Amyloid beta-dependent mitochondrial toxicity in mouse microglia requires P2X7 receptor expression and is prevented by nimodipine. Sci Rep (2019) 9(1): 6475. 10.1038/s41598-019-42931-2 31019207 PMC6482182 · DOI
  53. [72]Zuo H Wan Y. Metabolic Reprogramming in Mitochondria of Myeloid Cells. Cells (2019) 9(1): 1– 17. 10.3390/cells9010005 PMC7017304 31861356 · DOI
  54. [73]Jha AK Huang SC Sergushichev A Lampropoulou V Ivanova Y Loginicheva E. Network integration of parallel metabolic and transcriptional data reveals metabolic modules that regulate macrophage polarization. Immunity (2015) 42(3): 419–30. 10.1016/j.immuni.2015.02.005 25786174 · DOI · Paper page
  55. [74]Kaneko I Yamada N Sakuraba Y Kamenosono M Tutumi S. Suppression of Mitochondrial Succinate Dehydrogenase, a Primary Target of β-Amyloid, and Its Derivative Racemized at Ser Residue. J Neurochem (1995) 65(6): 2585–93. 10.1046/j.1471-4159.1995.65062585.x 7595555 · DOI
  56. [75]Konttinen H Ohtonen S Wojciechowski S Shakirzyanova A Caligola S Giugno R. PSEN1ΔE9, APPswe, and APOE4 confer disparate phenotypes in human iPSC-derived microglia. Stem Cell Rep (2019) 13(4): 669–83. 10.1016/j.stemcr.2019.08.004 PMC6829767 31522977 · DOI · Paper page
  57. [76]Reiman EM Caselli RJ Chen K Alexander GE Bandy D Frost J. Declining brain activity in cognitively normal apolipoprotein E epsilon 4 heterozygotes: A foundation for using positron emission tomography to efficiently test treatments to prevent Alzheimer’s disease. Proc Natl Acad Sci U S A (2001) 98(6): 3334–9. 10.1073/pnas.061509598 PMC30654 11248079 · DOI · Paper page
  58. [77]Lee J Choi J Wong GW Wolfgang MJ. Neurometabolic roles of ApoE and Ldl-R in mouse brain. J Bioenerg Biomembr (2016) 48(1): 13– 21. 10.1007/s10863-015-9636-6 26686234 PMC4733629 · DOI · Paper page
  59. [79]Yeh FL Wang Y Tom I Gonzalez LC Sheng M. TREM2 Binds to Apolipoproteins, Including APOE and CLU/APOJ, and Thereby Facilitates Uptake of Amyloid-Beta by Microglia. Neuron (2016) 91(2): 328–40. 10.1016/j.neuron.2016.06.015 27477018 · DOI · Paper page
  60. [80]Yuan P Condello C Keene CD Wang Y Bird TD Paul SM. TREM2 Haplodeficiency in Mice and Humans Impairs the Microglia Barrier Function Leading to Decreased Amyloid Compaction and Severe Axonal Dystrophy. Neuron (2016) 90(4): 724–39. 10.1016/j.neuron.2016.05.003 PMC4898967 27196974 · DOI · Paper page
  61. [81]Atagi Y Liu C-C Painter MM Chen X-F Verbeeck C Zheng H. Apolipoprotein E is a ligand for triggering receptor expressed on myeloid cells 2 (TREM2). J Biol Chem (2015) 290(43): 26043–50. 10.1074/jbc.M115.679043 PMC4646257 26374899 · DOI · Paper page
  62. [82]Götzl JK Brendel M Werner G Parhizkar S Sebastian Monasor L Kleinberger G. Opposite microglial activation stages upon loss of PGRN or TREM 2 result in reduced cerebral glucose metabolism. EMBO Mol Med (2019) 11(6): e9711. 10.1523/JNEUROSCI.2070-18.2019 31122931 PMC6554672 · DOI
  63. [83]Kleinberger G Brendel M Mracsko E Wefers B Groeneweg L Xiang X. The FTD-like syndrome causing TREM 2 T66M mutation impairs microglia function, brain perfusion, and glucose metabolism. EMBO J (2017) 36(13): 1837–53. 10.15252/embj.201796516 PMC5494459 28559417 · DOI
  64. [85]Monasor LS Müller SA Colombo AV Tanrioever G König J Roth S. Fibrillar Aβ triggers microglial proteome alterations and dysfunction in Alzheimer mouse models. Elife (2020) 9: e54083. 10.7554/eLife.54083 32510331 PMC7279888 · DOI · Paper page
  65. [86]Mela V Mota BC Milner M McGinley A Mills KH Kelly ÁM. Exercise-induced re-programming of age-related metabolic changes in microglia is accompanied by a reduction in senescent cells. Brain Behav Immun (2020) 87: 413–28. 10.1016/j.bbi.2020.01.012 31978523 · DOI
  66. [88]Bosch M Sánchez-Álvarez M Fajardo A Kapetanovic R Steiner B Dutra F. Mammalian lipid droplets are innate immune hubs integrating cell metabolism and host defense. Science (2020) 370(6514): 1– 12. 10.1126/science.aay8085 33060333 · DOI · Paper page
  67. [89]Brusco J Haas K. Interactions between mitochondria and the transcription factor myocyte enhancer factor 2 (MEF2) regulate neuronal structural and functional plasticity and metaplasticity. J Physiol (2015) 593(16): 3471–81. 10.1113/jphysiol.2014.282459 PMC4560579 25581818 · DOI
  68. [90]Geng J Sun X Wang P Zhang S Wang X Wu H. Kinases Mst1 and Mst2 positively regulate phagocytic induction of reactive oxygen species and bactericidal activity. Nat Immunol (2015) 16(11): 1142–52. 10.1038/ni.3268 PMC4618176 26414765 · DOI · Paper page
  69. [91]Feingold KR Shigenaga JK Kazemi MR McDonald CM Patzek SM Cross AS. Mechanisms of triglyceride accumulation in activated macrophages. J Leukoc Biol (2012) 92(4): 829–39. 10.1189/jlb.1111537 PMC3441312 22753953 · DOI
  70. [92]Freemerman AJ Johnson AR Sacks GN Milner JJ Kirk EL Troester MA. Metabolic reprogramming of macrophages: glucose transporter 1 (GLUT1)-mediated glucose metabolism drives a proinflammatory phenotype. J Biol Chem (2014) 289(11): 7884–96. 10.1074/jbc.M113.522037 PMC3953299 24492615 · DOI
  71. [93]Michl J Ohlbaum DJ Silverstein SC. 2-Deoxyglucose selectively inhibits Fc and complement receptor-mediated phagocytosis in mouse peritoneal macrophages II. Dissociation of the inhibitory effects of 2-deoxyglucose on phagocytosis and ATP generation. J Exp Med (1976) 144(6): 1484–93. 10.1084/jem.144.6.1484 PMC2190489 1003099 · DOI
  72. [94]Pavlou S Wang L Xu H Chen M. Higher phagocytic activity of thioglycollate-elicited peritoneal macrophages is related to metabolic status of the cells. J Inflamm (2017) 14(1): 4. 10.1186/s12950-017-0151-x PMC5301433 28203119 · DOI
  73. [95]Koo SJ Szczesny B Wan X Putluri N Garg NJ. Pentose Phosphate Shunt Modulates Reactive Oxygen Species and Nitric Oxide Production Controlling Trypanosoma cruzi in Macrophages. Front Immunol (2018) 9: 202. 10.3389/fimmu.2018.00202 29503646 PMC5820298 · DOI
  74. [96]Pan RY Ma J Kong XX Wang XF Li SS Qi XL. Sodium rutin ameliorates Alzheimer’s disease-like pathology by enhancing microglial amyloid-beta clearance. Sci Adv (2019) 5(2): eaau6328. 10.1126/sciadv.aau6328 30820451 PMC6393001 · DOI
  75. [97]Rubio-Araiz A Finucane OM Keogh S Lynch MA. Anti-TLR2 antibody triggers oxidative phosphorylation in microglia and increases phagocytosis of beta-amyloid. J Neuroinflamm (2018) 15(1): 247. 10.1186/s12974-018-1281-7 PMC6119264 30170611 · DOI
  76. [98]Fang EF Hou Y Palikaras K Adriaanse BA Kerr JS Yang B. Mitophagy inhibits amyloid-beta and tau pathology and reverses cognitive deficits in models of Alzheimer’s disease. Nat Neurosci (2019) 22(3): 401–12. 10.1038/s41593-018-0332-9 PMC6693625 30742114 · DOI · Paper page
  77. [100]Gibson MS Domingues N Vieira OV. Lipid and Non-lipid Factors Affecting Macrophage Dysfunction and Inflammation in Atherosclerosis. Front Physiol (2018) 9: 654. 10.3389/fphys.2018.00654 29997514 PMC6029489 · DOI
  78. [102]Broom GM Shaw IC Rucklidge JJ. The ketogenic diet as a potential treatment and prevention strategy for Alzheimer’s disease. Nutrition (2019) 60: 118–21. 10.1016/j.nut.2018.10.003 30554068 · DOI
  79. [103]Henderson ST Vogel JL Barr LJ Garvin F Jones JJ Costantini LC. Study of the ketogenic agent AC-1202 in mild to moderate Alzheimer’s disease: a randomized, double-blind, placebo-controlled, multicenter trial. Nutr Metab (Lond) (2009) 6: 31. 10.1186/1743-7075-6-31 19664276 PMC2731764 · DOI · Paper page
  80. [106]Taylor MK Sullivan DK Mahnken JD Burns JM Swerdlow RH. Feasibility and efficacy data from a ketogenic diet intervention in Alzheimer’s disease. Alzheimers Dement (N Y) (2018) 4: 28– 36. 10.1016/j.trci.2017.11.002 29955649 PMC6021549 · DOI
  81. [107]Yang X Cheng B. Neuroprotective and anti-inflammatory activities of ketogenic diet on MPTP-induced neurotoxicity. J Mol Neurosci (2010) 42(2): 145–53. 10.1007/s12031-010-9336-y 20333481 · DOI
  82. [108]Huang C Wang P Xu X Zhang Y Gong Y Hu W. The ketone body metabolite beta-hydroxybutyrate induces an antidepression-associated ramification of microglia via HDACs inhibition-triggered Akt-small RhoGTPase activation. Glia (2018) 66(2): 256–78. 10.1002/glia.23241 29058362 · DOI
  83. [109]Dupuis N Curatolo N Benoist JF Auvin S. Ketogenic diet exhibits anti-inflammatory properties. Epilepsia (2015) 56(7): e95–8. 10.1111/epi.13038 26011473 · DOI
  84. [112]Forstermann U Kleinert H. Nitric oxide synthase: expression and expressional control of the three isoforms. Naunyn Schmiedebergs Arch Pharmacol (1995) 352(4): 351–64. 10.1007/BF00172772 8532063 · DOI
  85. [113]Fodelianaki G Lansing F Bhattarai P Troullinaki M Zeballos MA Charalampopoulos I. Nerve Growth Factor modulates LPS - induced microglial glycolysis and inflammatory responses. Exp Cell Res (2019) 377(1-2): 10–6. 10.1016/j.yexcr.2019.02.023 30817930 · DOI
  86. [114]Birch AM Kelly ÁM. Lifelong environmental enrichment in the absence of exercise protects the brain from age-related cognitive decline. Neuropharmacology (2019) 145: 59– 74. 10.1016/j.neuropharm.2018.03.042 29630903 · DOI
  87. [115]Svensson M Andersson E Manouchehrian O Yang Y Deierborg T. Voluntary running does not reduce neuroinflammation or improve non-cognitive behavior in the 5xFAD mouse model of Alzheimer’s disease. Sci Rep (2020) 10(1): 1– 10. 10.1038/s41598-020-58309-8 31992814 PMC6987124 · DOI
  88. [116]Tapia-Rojas C Aranguiz F Varela-Nallar L Inestrosa NC. Voluntary Running Attenuates Memory Loss, Decreases Neuropathological Changes and Induces Neurogenesis in a Mouse Model of A lzheimer’s Disease. Brain Pathol (2016) 26(1): 62– 74. 10.1111/bpa.12255 25763997 PMC8029165 · DOI
  89. [117]Xu ZQ Zhang LQ Wang Q Marshall C Xiao N Gao JY. Aerobic Exercise Combined with Antioxidative Treatment does not Counteract Moderate-or Mid-Stage A lzheimer-Like Pathophysiology of APP/PS 1 Mice. CNS Neurosci Ther (2013) 19(10): 795– 803. 10.1111/cns.12139 23827013 PMC6493399 · DOI
  90. [118]Zhang J Guo Y Wang Y Song L Zhang R Du Y. Long-term treadmill exercise attenuates Aβ burdens and astrocyte activation in APP/PS1 mouse model of Alzheimer’s disease. Neurosci Lett (2018) 666: 70–7. 10.1016/j.neulet.2017.12.025 29246793 · DOI
  91. [119]Gibbons T. Enhancing learning and memory in the aged: Interactions between dietary supplementation and exercise. Urbana: University of Illinois (2014). http://hdl.handle.net/2142/49842Ñ20.
  92. [121]Caslin HL Taruselli MT Haque T Pondicherry N Baldwin EA Barnstein BO. Inhibiting Glycolysis and ATP Production Attenuates IL-33-Mediated Mast Cell Function and Peritonitis. Front Immunol (2018) 9: 3026. 10.3389/fimmu.2018.03026 30619366 PMC6305324 · DOI
  93. [122]Poulain L Sujobert P Zylbersztejn F Barreau S Stuani L Lambert M. High mTORC1 activity drives glycolysis addiction and sensitivity to G6PD inhibition in acute myeloid leukemia cells. Leukemia (2017) 31(11): 2326–35. 10.1038/leu.2017.81 28280275 · DOI · Paper page
  94. [124]Ou Z Kong X Sun X He X Zhang L Gong Z. Metformin treatment prevents amyloid plaque deposition and memory impairment in APP/PS1 mice. Brain Behav Immun (2018) 69: 351–63. 10.1016/j.bbi.2017.12.009 29253574 · DOI
  95. [125]Peng Q Malhotra S Torchia JA Kerr WG Coggeshall KM Humphrey MB. TREM2- and DAP12-dependent activation of PI3K requires DAP10 and is inhibited by SHIP1. Sci Signal (2010) 3(122): ra38. 10.1126/scisignal.2000500 20484116 PMC2900152 · DOI · Paper page
  96. [128]Gulyás B Makkai B Nagy K Vas Á Kása P Andersson J. In vitro evidence for competitive tspo binding of the imaging biomarker candidates vinpocetine and two iodinated daa1106 analogues in post mortem autoradiography experiments on whole hemisphere human brain slices. Curr Radiopharm (2009) 2(1): 42–8. 10.2174/1874471010902010042 · DOI
  97. [129]Gong J Szego ÉM Leonov A Benito E Becker S Fischer A. Translocator protein ligand protects against neurodegeneration in the MPTP mouse model of Parkinsonism. J Neurosci (2019) 39(19): 3752–69. 10.1523/JNEUROSCI.2070-18.2019 PMC6510339 30796158 · DOI
  98. [130]Leva G Klein C Benyounes J Hallé F Bihel F Collongues N. The translocator protein ligand XBD173 improves clinical symptoms and neuropathological markers in the SJL/J mouse model of multiple sclerosis. Biochim Biophys Acta (BBA)-Mol Basis Dis (2017) 1863(12): 3016–27. 10.1016/j.bbadis.2017.09.007 28899788 · DOI
  99. [131]Barron AM Garcia-Segura LM Caruso D Jayaraman A Lee JW Melcangi RC. Ligand for translocator protein reverses pathology in a mouse model of Alzheimer’s disease. J Neurosci (2013) 33(20): 8891–7. 10.1523/JNEUROSCI.1350-13.2013 PMC3733563 23678130 · DOI
  100. [132]Yao R Pan R Shang C Li X Cheng J Xu J. Translocator Protein 18 kDa (TSPO) Deficiency Inhibits Microglial Activation and Impairs Mitochondrial Function. Front Pharmacol (2020) 11: 986. 10.3389/fphar.2020.00986 32695005 PMC7339871 · DOI · Paper page
  101. [133]Tu LN Zhao AH Hussein M Stocco DM Selvaraj V. Translocator Protein (TSPO) Affects Mitochondrial Fatty Acid Oxidation in Steroidogenic Cells. Endocrinology (2016) 157(3): 1110–21. 10.1210/en.2015-1795 PMC4769361 26741196 · DOI
  102. [134]Zeineh N Denora N Laquintana V Franco M Weizman A Gavish M. Efficaciousness of Low Affinity Compared to High Affinity TSPO Ligands in the Inhibition of Hypoxic Mitochondrial Cellular Damage Induced by Cobalt Chloride in Human Lung H1299 Cells. Biomedicines (2020) 8(5): 1– 18. 10.3390/biomedicines8050106 PMC7277862 32370132 · DOI

Cited by

Sorted by citations

Authors
Fairley, L. H., Wong, J. H., & Barron, A. M.
Affiliations
Nanyang Technological University (SG)
Corresponding author
Barron, Anna M.
ORCID
Venue
Frontiers in Immunology
Publisher
Frontiers Media SA
Published
2021-02-25
Volume
12
Pages
624538-624538
ISSN
1664-3224 (ISSN-L)
DOI
10.3389/fimmu.2021.624538
PMC
PMC7947196
OpenAlex
W3129406070
Cited by
120
References
30
Citations by year
2026: 24 · 2025: 27 · 2024: 24 · 2023: 22 · 2022: 18 · 2021: 5
FWCI
2.02
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Immunology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • HAL (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • DR-NTU (Nanyang Technological University) (submittedVersion, cc-by)
Funders
  • Alzheimer's Association
  • Nanyang Technological University
  • Ministry of Education - Singapore
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
Keywords
Alzheimer's disease, microglia, mitochondrial metabolism, immunometabolism, innate immunity, neuroinflammation, metabolic reprogramming, amyloid-beta, tau protein, neurodegeneration
MeSH terms
Alzheimer Disease, Animals, Brain, Energy Metabolism, Humans, Immunity, Innate, Mitochondria, Nerve Degeneration, Amyloid beta-Peptides, tau Proteins, Microglia

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