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Journal of Neuroinflammation
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Open Access 01-12-2024 | Alzheimer's Disease | Review

Fueling neurodegeneration: metabolic insights into microglia functions

Authors: Mohammadamin Sadeghdoust, Aysika Das, Deepak Kumar Kaushik

Published in: Journal of Neuroinflammation | Issue 1/2024

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Abstract

Microglia, the resident immune cells of the central nervous system, emerge in the brain during early embryonic development and persist throughout life. They play essential roles in brain homeostasis, and their dysfunction contributes to neuroinflammation and the progression of neurodegenerative diseases. Recent studies have uncovered an intricate relationship between microglia functions and metabolic processes, offering fresh perspectives on disease mechanisms and possible treatments. Despite these advancements, there are still significant gaps in our understanding of how metabolic dysregulation affects microglial phenotypes in these disorders. This review aims to address these gaps, laying the groundwork for future research on the topic. We specifically examine how metabolic shifts in microglia, such as the transition from oxidative phosphorylation and mitochondrial metabolism to heightened glycolysis during proinflammatory states, impact the disease progression in Alzheimer’s disease, multiple sclerosis, Parkinson’s disease, amyotrophic lateral sclerosis, and Huntington’s disease. Additionally, we explore the role of iron, fatty and amino acid metabolism in microglial homeostasis and repair. Identifying both distinct and shared metabolic adaptations in microglia across neurodegenerative diseases could reveal common therapeutic targets and provide a deeper understanding of disease-specific mechanisms underlying multiple CNS disorders.
Literature
1.
Kierdorf K, Erny D, Goldmann T, Sander V, Schulz C, Perdiguero EG, et al. Microglia emerge from erythromyeloid precursors via Pu. 1-and Irf8-dependent pathways. Nat Neurosci. 2013;16(3):273–80.PubMedCrossRef
2.
Perry V, Hume DA, Gordon S. Immunohistochemical localization of macrophages and microglia in the adult and developing mouse brain. Neuroscience. 1985;15(2):313–26.PubMedCrossRef
3.
Nimmerjahn A, Kirchhoff F, Helmchen F. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science. 2005;308(5726):1314–8.PubMedCrossRef
4.
Ransohoff RM, Perry VH. Microglial physiology: unique stimuli, specialized responses. Annu Rev Immunol. 2009;27:119–45.PubMedCrossRef
5.
Davalos D, Grutzendler J, Yang G, Kim JV, Zuo Y, Jung S, et al. ATP mediates rapid microglial response to local brain injury in vivo. Nat Neurosci. 2005;8(6):752–8.PubMedCrossRef
6.
Hickman SE, Kingery ND, Ohsumi TK, Borowsky ML, Wang L-c, Means TK, et al. The microglial sensome revealed by direct RNA sequencing. Nat Neurosci. 2013;16(12):1896–905.PubMedPubMedCentralCrossRef
7.
Perry VH, Nicoll JA, Holmes C. Microglia in neurodegenerative disease. Nat Reviews Neurol. 2010;6(4):193–201.CrossRef
8.
Agrawal M. Molecular basis of chronic neurodegeneration. Clinical molecular medicine: Elsevier; 2020. pp. 447–60.
9.
Erkkinen MG, Kim M-O, Geschwind MD. Clinical neurology and epidemiology of the major neurodegenerative diseases. Cold Spring Harb Perspect Biol. 2018;10(4):a033118.PubMedPubMedCentralCrossRef
10.
Nichols E, Szoeke CE, Vollset SE, Abbasi N, Abd-Allah F, Abdela J, et al. Global, regional, and national burden of Alzheimer’s disease and other dementias, 1990–2016: a systematic analysis for the global burden of Disease Study 2016. Lancet Neurol. 2019;18(1):88–106.CrossRef
11.
Hou Y, Dan X, Babbar M, Wei Y, Hasselbalch SG, Croteau DL, et al. Ageing as a risk factor for neurodegenerative disease. Nat Reviews Neurol. 2019;15(10):565–81.CrossRef
12.
Navarro V, Sanchez-Mejias E, Jimenez S, Muñoz-Castro C, Sanchez-Varo R, Davila JC, et al. Microglia in Alzheimer’s disease: activated, dysfunctional or degenerative. Front Aging Neurosci. 2018;10:357752.CrossRef
13.
Krasemann S, Madore C, Cialic R, Baufeld C, Calcagno N, El Fatimy R, et al. The TREM2-APOE pathway drives the transcriptional phenotype of dysfunctional microglia in neurodegenerative diseases. Immunity. 2017;47(3):566–81. e9.PubMedPubMedCentralCrossRef
14.
Yong VW. Microglia in multiple sclerosis: protectors turn destroyers. Neuron. 2022;110(21):3534–48.PubMedCrossRef
15.
16.
Lynch MA. Can the emerging field of immunometabolism provide insights into neuroinflammation? Prog Neurobiol. 2020;184:101719.PubMedCrossRef
17.
Benarroch E. What is the role of Microglial metabolism in inflammation and neurodegeneration? Neurology. 2022;99(3):99–105.PubMedCrossRef
18.
Kaushik DK, Yong VW. Metabolic needs of brain-infiltrating leukocytes and microglia in multiple sclerosis. J Neurochem. 2021;158(1):14–24.PubMedCrossRef
19.
Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 1991;82(4):239–59.PubMedCrossRef
20.
Hardy JA, Higgins GA. Alzheimer’s disease: the amyloid cascade hypothesis. Science. 1992;256(5054):184–5.PubMedCrossRef
21.
Lai AY, McLaurin J. Clearance of amyloid-β peptides by microglia and macrophages: the issue of what, when and where. Future Neurol. 2012;7(2):165–76.PubMedPubMedCentralCrossRef
22.
Pereira JB, Janelidze S, Strandberg O, Whelan CD, Zetterberg H, Blennow K, et al. Microglial activation protects against accumulation of tau aggregates in nondemented individuals with underlying Alzheimer’s disease pathology. Nat Aging. 2022;2(12):1138–44.PubMedPubMedCentralCrossRef
23.
Condello C, Yuan P, Schain A, Grutzendler J. Microglia constitute a barrier that prevents neurotoxic protofibrillar Aβ42 hotspots around plaques. Nat Commun. 2015;6(1):6176.PubMedCrossRef
24.
Ising C, Venegas C, Zhang S, Scheiblich H, Schmidt SV, Vieira-Saecker A, et al. NLRP3 inflammasome activation drives tau pathology. Nature. 2019;575(7784):669–73.PubMedPubMedCentralCrossRef
25.
Heneka MT, Kummer MP, Stutz A, Delekate A, Schwartz S, Vieira-Saecker A, et al. NLRP3 is activated in Alzheimer’s disease and contributes to pathology in APP/PS1 mice. Nature. 2013;493(7434):674–8.PubMedCrossRef
26.
Gordon R, Albornoz EA, Christie DC, Langley MR, Kumar V, Mantovani S, et al. Inflammasome inhibition prevents α-synuclein pathology and dopaminergic neurodegeneration in mice. Sci Transl Med. 2018;10(465):eaah4066.PubMedPubMedCentralCrossRef
27.
Cheng J, Zhang R, Xu Z, Ke Y, Sun R, Yang H, et al. Early glycolytic reprogramming controls microglial inflammatory activation. J Neuroinflamm. 2021;18(1):129.CrossRef
28.
Zhang Y, Chen K, Sloan SA, Bennett ML, Scholze AR, O’Keeffe S, et al. An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex. J Neurosci. 2014;34(36):11929–47.PubMedPubMedCentralCrossRef
29.
Payne J, Maher F, Simpson I, Mattice L, Davies P. Glucose transporter glut 5 expression in microglial cells. Glia. 1997;21(3):327–31.PubMedCrossRef
30.
Wang L, Pavlou S, Du X, Bhuckory M, Xu H, Chen M. Glucose transporter 1 critically controls microglial activation through facilitating glycolysis. Mol Neurodegeneration. 2019;14:1–15.CrossRef
31.
32.
Wang L, Pavlou S, Du X, Bhuckory M, Xu H, Chen M. Glucose transporter 1 critically controls microglial activation through facilitating glycolysis. Mol Neurodegeneration. 2019;14(1):1–15.CrossRef
33.
Kalsbeek MJ, Mulder L, Yi C-X. Microglia energy metabolism in metabolic disorder. Mol Cell Endocrinol. 2016;438:27–35.PubMedCrossRef
34.
Biswas J, Gupta S, Verma DK, Gupta P, Singh A, Tiwari S, et al. Involvement of glucose related energy crisis and endoplasmic reticulum stress: insinuation of streptozotocin induced Alzheimer’s like pathology. Cell Signal. 2018;42:211–26.PubMedCrossRef
35.
Harr SD, Simonian NA, Hyman BT. Functional alterations in Alzheimer’s disease: decreased glucose transporter 3 immunoreactivity in the perforant pathway terminal zone. J Neuropathology Experimental Neurol. 1995;54(1):38–41.CrossRef
36.
Simpson IA, Chundu KR, Davies-Hill T, Honer WG, Davies P. Decreased concentrations of GLUT1 and GLUT3 glucose transporters in the brains of patients with Alzheimer’s disease. Annals Neurology: Official J Am Neurol Association Child Neurol Soc. 1994;35(5):546–51.CrossRef
37.
Brendel M, Probst F, Jaworska A, Overhoff F, Korzhova V, Albert NL, et al. Glial activation and glucose metabolism in a transgenic amyloid mouse model: a triple-tracer PET study. J Nucl Med. 2016;57(6):954–60.PubMedCrossRef
38.
Johnson EC, Dammer EB, Duong DM, Ping L, Zhou M, Yin L, et al. 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.PubMedPubMedCentralCrossRef
39.
Backes H, Walberer M, Ladwig A, Rueger MA, Neumaier B, Endepols H, et al. Glucose consumption of inflammatory cells masks metabolic deficits in the brain. NeuroImage. 2016;128:54–62.PubMedCrossRef
40.
Warburg O. The metabolism of carcinoma cells. J Cancer Res. 1925;9(1):148–63.CrossRef
41.
Schuster S, Boley D, Möller P, Stark H, Kaleta C. Mathematical models for explaining the Warburg effect: a review focussed on ATP and biomass production. Biochem Soc Trans. 2015;43(6):1187–94.PubMedCrossRef
42.
43.
Liang X, Wang Z, Dai Z, Zhang H, Zhang J, Luo P, et al. Glioblastoma glycolytic signature predicts unfavorable prognosis, immunological heterogeneity, and ENO1 promotes microglia M2 polarization and cancer cell malignancy. Cancer Gene Ther. 2023;30(3):481–96.PubMed
44.
Bernier L-P, York EM, MacVicar BA. Immunometabolism in the brain: how metabolism shapes microglial function. Trends Neurosci. 2020;43(11):854–69.PubMedCrossRef
45.
Baik SH, Kang S, Lee W, Choi H, Chung S, Kim J-I, et al. A breakdown in metabolic reprogramming causes microglia dysfunction in Alzheimer’s disease. Cell Metabol. 2019;30(3):493–507. e6.CrossRef
46.
Zhao Y, Xu H. Microglial lactate metabolism as a potential therapeutic target for Alzheimer’s disease. Mol Neurodegeneration. 2022;17(1):1–3.CrossRef
47.
Andersson AK, Rönnbäck L, Hansson E. Lactate induces tumour necrosis factor-α, interleukin‐6 and interleukin‐1β release in microglial‐and astroglial‐enriched primary cultures. J Neurochem. 2005;93(5):1327–33.PubMedCrossRef
48.
Zhang D, Tang Z, Huang H, Zhou G, Cui C, Weng Y, et al. Metabolic regulation of gene expression by histone lactylation. Nature. 2019;574(7779):575–80.PubMedPubMedCentralCrossRef
49.
Pan R-Y, He L, Zhang J, Liu X, Liao Y, Gao J, et al. Positive feedback regulation of microglial glucose metabolism by histone H4 lysine 12 lactylation in Alzheimer’s disease. Cell Metabol. 2022;34(4):634–48. e6.CrossRef
50.
Hsieh CL, Koike M, Spusta SC, Niemi EC, Yenari M, Nakamura MC, et al. A role for TREM2 ligands in the phagocytosis of apoptotic neuronal cells by microglia. J Neurochem. 2009;109(4):1144–56.PubMedPubMedCentralCrossRef
51.
Keren-Shaul H, Spinrad A, Weiner A, Matcovitch-Natan O, Dvir-Szternfeld R, Ulland TK, et al. A unique microglia type associated with restricting development of Alzheimer’s disease. Cell. 2017;169(7):1276–90. e17.PubMedCrossRef
52.
Deczkowska A, Keren-Shaul H, Weiner A, Colonna M, Schwartz M, Amit I. Disease-associated microglia: a universal immune sensor of neurodegeneration. Cell. 2018;173(5):1073–81.PubMedCrossRef
53.
Xing J, Titus AR, Beth Humphrey M. The TREM2-DAP12 signaling pathway in Nasu–Hakola disease: a molecular genetics perspective. Res Rep Biochem. 2015:89–100.
54.
Kleinberger G, Brendel M, Mracsko E, Wefers B, Groeneweg L, Xiang X, et al. The FTD-like syndrome causing TREM 2 T66M mutation impairs microglia function, brain perfusion, and glucose metabolism. EMBO J. 2017;36(13):1837–53.PubMedPubMedCentralCrossRef
55.
Ulland TK, Song WM, Huang SC-C, Ulrich JD, Sergushichev A, Beatty WL, et al. TREM2 maintains microglial metabolic fitness in Alzheimer’s disease. Cell. 2017;170(4):649–63. e13.PubMedPubMedCentralCrossRef
56.
57.
58.
Loving BA, Bruce KD. Lipid and lipoprotein metabolism in microglia. Front Physiol. 2020;11:526534.CrossRef
59.
Chausse B, Kakimoto PA, Kann O, editors. Microglia and lipids: how metabolism controls brain innate immunity. Seminars in cell & developmental biology. Elsevier; 2021.
60.
Fitz NF, Nam KN, Wolfe CM, Letronne F, Playso BE, Iordanova BE, et al. Phospholipids of APOE lipoproteins activate microglia in an isoform-specific manner in preclinical models of Alzheimer’s disease. Nat Commun. 2021;12(1):3416.PubMedPubMedCentralCrossRef
61.
Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small G, et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science. 1993;261(5123):921–3.PubMedCrossRef
62.
Kelly B, Pearce EL. Amino assets: how amino acids support immunity. Cell Metabol. 2020;32(2):154–75.CrossRef
63.
64.
Vazquez-Valls E, Flores-Soto M, Chaparro-Huerta V, Torres-Mendoza B, Gudiño-Cabrera G, Rivera-Cervantes M, et al. HIF-1α expression in the hippocampus and peripheral macrophages after glutamate-induced excitotoxicity. J Neuroimmunol. 2011;238(1–2):12–8.PubMedCrossRef
65.
Tannahill G, Curtis A, Adamik J, Palsson-McDermott E, McGettrick A, Goel G, et al. Succinate is an inflammatory signal that induces IL-1β through HIF-1α. Nature. 2013;496(7444):238–42.PubMedPubMedCentralCrossRef
66.
Lukyanova L, Kirova YI, Germanova E. The role of succinate in regulation of immediate HIF-1α expression in hypoxia. Bull Exp Biol Med. 2018;164:298–303.PubMedCrossRef
67.
Gao G, Zhao S, Xia X, Li C, Li C, Ji C, et al. Glutaminase C regulates microglial activation and pro-inflammatory exosome release: relevance to the pathogenesis of Alzheimer’s disease. Front Cell Neurosci. 2019;13:264.PubMedPubMedCentralCrossRef
68.
Gao G, Li C, Zhu J, Wang Y, Huang Y, Zhao S, et al. Glutaminase 1 regulates neuroinflammation after cerebral ischemia through enhancing microglial activation and pro-inflammatory exosome release. Front Immunol. 2020;11:161.PubMedPubMedCentralCrossRef
69.
Kono M, Yoshida N, Maeda K, Suárez-Fueyo A, Kyttaris VC, Tsokos GC. Glutaminase 1 inhibition reduces glycolysis and ameliorates lupus‐like disease in MRL/lpr mice and experimental autoimmune encephalomyelitis. Arthritis Rheumatol. 2019;71(11):1869–78.PubMedPubMedCentralCrossRef
70.
Nakajima K, Kanamatsu T, Takezawa Y, Kohsaka S. Up-regulation of glutamine synthesis in microglia activated with endotoxin. Neurosci Lett. 2015;591:99–104.PubMedCrossRef
71.
72.
Maddison DC, Giorgini F, editors. The kynurenine pathway and neurodegenerative disease. Seminars in cell & developmental biology. Elsevier; 2015.
73.
Pallotta MT, Rossini S, Suvieri C, Coletti A, Orabona C, Macchiarulo A, et al. Indoleamine 2, 3-dioxygenase 1 (IDO1): an up‐to‐date overview of an eclectic immunoregulatory enzyme. FEBS J. 2022;289(20):6099–118.PubMedCrossRef
74.
Feng W, Wang Y, Liu Z-Q, Zhang X, Han R, Miao Y-Z, et al. Microglia activation contributes to quinolinic acid-induced neuronal excitotoxicity through TNF-α. Apoptosis. 2017;22:696–709.PubMedCrossRef
75.
Rahman A, Ting K, Cullen KM, Braidy N, Brew BJ, Guillemin GJ. The excitotoxin quinolinic acid induces tau phosphorylation in human neurons. PLoS ONE. 2009;4(7):e6344.PubMedPubMedCentralCrossRef
76.
Alachkar A, Agrawal S, Baboldashtian M, Nuseir K, Salazar J, Agrawal A. L-methionine enhances neuroinflammation and impairs neurogenesis: implication for Alzheimer’s disease. J Neuroimmunol. 2022;366:577843.PubMedCrossRef
77.
Zhao Y, Dong X, Chen B, Zhang Y, Meng S, Guo F, et al. Blood levels of circulating methionine components in Alzheimer’s disease and mild cognitive impairment: a systematic review and meta-analysis. Front Aging Neurosci. 2022;14:934070.PubMedPubMedCentralCrossRef
78.
Miller AL. The methionine-homocysteine cycle and its effects on cognitive diseases.(Homocysteine & Cognitive). Altern Med Rev. 2003;8(1):7–20.PubMed
79.
Rath M, Müller I, Kropf P, Closs EI, Munder M. Metabolism via arginase or nitric oxide synthase: two competing arginine pathways in macrophages. Front Immunol. 2014;5:532.PubMedPubMedCentralCrossRef
80.
Caldwell RW, Rodriguez PC, Toque HA, Narayanan SP, Caldwell RB. Arginase: a multifaceted enzyme important in health and disease. Physiol Rev. 2018;98(2):641–65.PubMedPubMedCentralCrossRef
81.
Kan MJ, Lee JE, Wilson JG, Everhart AL, Brown CM, Hoofnagle AN, et al. Arginine deprivation and immune suppression in a mouse model of Alzheimer’s disease. J Neurosci. 2015;35(15):5969–82.PubMedPubMedCentralCrossRef
82.
Ma C, Hunt JB, Kovalenko A, Liang H, Selenica M-LB, Orr MB, et al. Myeloid arginase 1 insufficiency exacerbates amyloid-β associated neurodegenerative pathways and glial signatures in a mouse model of Alzheimer’s disease: a targeted transcriptome analysis. Front Immunol. 2021;12:628156.PubMedPubMedCentralCrossRef
83.
Urrutia P, Aguirre P, Esparza A, Tapia V, Mena NP, Arredondo M, et al. Inflammation alters the expression of DMT 1, FPN 1 and hepcidin, and it causes iron accumulation in central nervous system cells. J Neurochem. 2013;126(4):541–9.PubMedCrossRef
84.
Bishop GM, Dang TN, Dringen R, Robinson SR. Accumulation of non-transferrin-bound iron by neurons, astrocytes, and microglia. Neurotox Res. 2011;19:443–51.PubMedCrossRef
85.
Song N, Wang J, Jiang H, Xie J. Astroglial and microglial contributions to iron metabolism disturbance in Parkinson’s disease. Biochim et Biophys Acta (BBA)-Molecular Basis Disease. 2018;1864(3):967–73.CrossRef
86.
Zeineh MM, Chen Y, Kitzler HH, Hammond R, Vogel H, Rutt BK. Activated iron-containing microglia in the human hippocampus identified by magnetic resonance imaging in Alzheimer disease. Neurobiol Aging. 2015;36(9):2483–500.PubMedPubMedCentralCrossRef
87.
van Duijn S, Bulk M, van Duinen SG, Nabuurs RJ, van Buchem MA, van der Weerd L, et al. Cortical iron reflects severity of Alzheimer’s disease. J Alzheimers Dis. 2017;60(4):1533–45.PubMedPubMedCentralCrossRef
88.
Holland R, McIntosh A, Finucane O, Mela V, Rubio-Araiz A, Timmons G, et al. Inflammatory microglia are glycolytic and iron retentive and typify the microglia in APP/PS1 mice. Brain Behav Immun. 2018;68:183–96.PubMedCrossRef
89.
McIntosh A, Mela V, Harty C, Minogue AM, Costello DA, Kerskens C, et al. 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.PubMedPubMedCentralCrossRef
90.
The Multiple Sclerosis International Federation, Atlas of MS, 3rd Edition. (September 2020).
91.
Tortorella C, Bellacosa A, Paolicelli D, Fuiani A, Di Monte E, Simone IL, et al. Age-related gadolinium-enhancement of MRI brain lesions in multiple sclerosis. J Neurol Sci. 2005;239(1):95–9.PubMedCrossRef
92.
Giovannoni G, Silver N, Good C, Miller D, Thompson E. Immunological time-course of gadolinium-enhancing MRI lesions in patients with multiple sclerosis. Eur Neurol. 2000;44(4):222–8.PubMedCrossRef
93.
Brück W, Porada P, Poser S, Rieckmann P, Hanefeld F, Kretzschmarch HA, et al. Monocyte/macrophage differentiation in early multiple sclerosis lesions. Annals Neurology: Official J Am Neurol Association Child Neurol Soc. 1995;38(5):788–96.CrossRef
94.
Guerrier T, Labalette M, Launay D, Lee-Chang C, Outteryck O, Lefèvre G, et al. Proinflammatory B-cell profile in the early phases of MS predicts an active disease. Neurology: Neuroimmunol Neuroinflammation. 2017;5(2):e431.
95.
Murphy ÁC, Lalor SJ, Lynch MA, Mills KH. Infiltration of Th1 and Th17 cells and activation of microglia in the CNS during the course of experimental autoimmune encephalomyelitis. Brain Behav Immun. 2010;24(4):641–51.PubMedCrossRef
96.
Machado-Santos J, Saji E, Tröscher AR, Paunovic M, Liblau R, Gabriely G, et al. The compartmentalized inflammatory response in the multiple sclerosis brain is composed of tissue-resident CD8 + T lymphocytes and B cells. Brain. 2018;141(7):2066–82.PubMedPubMedCentralCrossRef
97.
Lassmann H. Multiple sclerosis pathology. Cold Spring Harbor Perspect Med. 2018;8(3):a028936.CrossRef
98.
Prineas JW, Parratt JD. Oligodendrocytes and the early multiple sclerosis lesion. Ann Neurol. 2012;72(1):18–31.PubMedCrossRef
99.
Wucherpfennig KW, Strominger JL. Molecular mimicry in T cell-mediated autoimmunity: viral peptides activate human T cell clones specific for myelin basic protein. Cell. 1995;80(5):695–705.PubMedPubMedCentralCrossRef
100.
Maghzi A-H, Borazanci A, McGee J, Alexander JS, Gonzalez-Toledo E, Minagar A. Multiple sclerosis: pathophysiology, clinical features, diagnosis, and management. Neuroinflammation: Elsevier; 2011. pp. 1–23.
101.
102.
Berglund R, Guerreiro-Cacais AO, Adzemovic MZ, Zeitelhofer M, Lund H, Ewing E, et al. Microglial autophagy–associated phagocytosis is essential for recovery from neuroinflammation. Sci Immunol. 2020;5(52):eabb5077.PubMedCrossRef
103.
Chéret C, Gervais A, Lelli A, Colin C, Amar L, Ravassard P, et al. Neurotoxic activation of microglia is promoted by a nox1-dependent NADPH oxidase. J Neurosci. 2008;28(46):12039–51.PubMedPubMedCentralCrossRef
104.
Correale J. The role of microglial activation in disease progression. Multiple Scler J. 2014;20(10):1288–95.CrossRef
105.
Broadwater L, Pandit A, Clements R, Azzam S, Vadnal J, Sulak M, et al. Analysis of the mitochondrial proteome in multiple sclerosis cortex. Biochim et Biophys Acta (BBA)-Molecular Basis Disease. 2011;1812(5):630–41.CrossRef
106.
Talla V, Koilkonda R, Porciatti V, Chiodo V, Boye SL, Hauswirth WW, et al. Complex I subunit gene therapy with NDUFA6 ameliorates neurodegeneration in EAE. Investig Ophthalmol Vis Sci. 2015;56(2):1129–40.CrossRef
107.
Regenold WT, Phatak P, Makley MJ, Stone RD, Kling MA. Cerebrospinal fluid evidence of increased extra-mitochondrial glucose metabolism implicates mitochondrial dysfunction in multiple sclerosis disease progression. J Neurol Sci. 2008;275(1–2):106–12.PubMedPubMedCentralCrossRef
108.
Nijland PG, Molenaar RJ, van der Pol SM, van der Valk P, van Noorden CJ, de Vries HE, et al. Differential expression of glucose-metabolizing enzymes in multiple sclerosis lesions. Acta Neuropathol Commun. 2015;3:1–13.CrossRef
109.
Keytsman C, Eijnde BO, Hansen D, Verboven K, Wens I. Elevated cardiovascular risk factors in multiple sclerosis. Multiple Scler Relat Disorders. 2017;17:220–3.CrossRef
110.
Kolln J, Ren H-M, Da R-R, Zhang Y, Spillner E, Olek M, et al. Triosephosphate isomerase-and glyceraldehyde-3-phosphate dehydrogenase-reactive autoantibodies in the cerebrospinal fluid of patients with multiple sclerosis. J Immunol. 2006;177(8):5652–8.PubMedCrossRef
111.
Royds JA, Timperley WR, Taylor CB. Levels of enolase and other enzymes in the cerebrospinal fluid as indices of pathological change. J Neurol Neurosurg Psychiatry. 1981;44(12):1129–35.PubMedPubMedCentralCrossRef
112.
Nijland PG, Michailidou I, Witte ME, Mizee MR, van der Pol SM, van Het Hof B, et al. Cellular distribution of glucose and monocarboxylate transporters in human brain white matter and multiple sclerosis lesions. Glia. 2014;62(7):1125–41.PubMedCrossRef
113.
Fantin VR, St-Pierre J, Leder P. Attenuation of LDH-A expression uncovers a link between glycolysis, mitochondrial physiology, and tumor maintenance. Cancer Cell. 2006;9(6):425–34.PubMedCrossRef
114.
Kaushik DK, Bhattacharya A, Mirzaei R, Rawji KS, Ahn Y, Rho JM, et al. Enhanced glycolytic metabolism supports transmigration of brain-infiltrating macrophages in multiple sclerosis. J Clin Investig. 2019;129(8):3277–92.PubMedPubMedCentralCrossRef
115.
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.PubMedCrossRef
116.
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):1559.PubMedPubMedCentralCrossRef
117.
Li Y, Lu B, Sheng L, Zhu Z, Sun H, Zhou Y, et al. Hexokinase 2-dependent hyperglycolysis driving microglial activation contributes to ischemic brain injury. J Neurochem. 2018;144(2):186–200.PubMedCrossRef
118.
Jha AK, Huang SC-C, Sergushichev A, Lampropoulou V, Ivanova Y, Loginicheva E, et al. Network integration of parallel metabolic and transcriptional data reveals metabolic modules that regulate macrophage polarization. Immunity. 2015;42(3):419–30.PubMedCrossRef
119.
Testa G, Staurenghi E, Zerbinati C, Gargiulo S, Iuliano L, Giaccone G, et al. Changes in brain oxysterols at different stages of Alzheimer’s disease: their involvement in neuroinflammation. Redox Biol. 2016;10:24–33.PubMedPubMedCentralCrossRef
120.
121.
McComb M, Browne RW, Bhattacharya S, Bodziak ML, Jakimovski D, Weinstock-Guttman B, et al. The cholesterol autoxidation products, 7-ketocholesterol and 7β-hydroxycholesterol are associated with serum neurofilaments in multiple sclerosis. Multiple Scler Relat Disorders. 2021;50:102864.CrossRef
122.
Diestel A, Aktas O, Hackel D, Häke I, Meier S, Raine CS, et al. Activation of microglial poly (ADP-ribose)-polymerase-1 by cholesterol breakdown products during neuroinflammation: a link between demyelination and neuronal damage. J Exp Med. 2003;198(11):1729–40.PubMedPubMedCentralCrossRef
123.
Kauppinen TM, Swanson RA. Poly (ADP-ribose) polymerase-1 promotes microglial activation, proliferation, and matrix metalloproteinase-9-mediated neuron death. J Immunol. 2005;174(4):2288–96.PubMedCrossRef
124.
Bjørnevik K, Chitnis T, Ascherio A, Munger KL. Polyunsaturated fatty acids and the risk of multiple sclerosis. Multiple Scler J. 2017;23(14):1830–8.CrossRef
125.
Hopperton KE, Trépanier M-O, Giuliano V, Bazinet RP. Brain omega-3 polyunsaturated fatty acids modulate microglia cell number and morphology in response to intracerebroventricular amyloid-β 1–40 in mice. J Neuroinflamm. 2016;13(1):1–18.CrossRef
126.
Sun W, Wang Q, Zhang R, Zhang N. Ketogenic diet attenuates neuroinflammation and induces conversion of M1 microglia to M2 in an EAE model of multiple sclerosis by regulating the NF-κB/NLRP3 pathway and inhibiting HDAC3 and P2X7R activation. Food Funct. 2023;14(15):7247–69.PubMedCrossRef
127.
Piccio L, Buonsanti C, Cella M, Tassi I, Schmidt RE, Fenoglio C, et al. Identification of soluble TREM-2 in the cerebrospinal fluid and its association with multiple sclerosis and CNS inflammation. Brain. 2008;131(11):3081–91.PubMedPubMedCentralCrossRef
128.
Qu S, Hu S, Xu H, Wu Y, Ming S, Zhan X et al. TREM-2 drives development of multiple sclerosis by promoting pathogenic Th17 polarization. Neurosci Bull. 2023:1–18.
129.
Dong Y, D’Mello C, Pinsky W, Lozinski BM, Kaushik DK, Ghorbani S, et al. Oxidized phosphatidylcholines found in multiple sclerosis lesions mediate neurodegeneration and are neutralized by microglia. Nat Neurosci. 2021;24(4):489–503.PubMedCrossRef
130.
Takahashi K, Prinz M, Stagi M, Chechneva O, Neumann H. TREM2-transduced myeloid precursors mediate nervous tissue debris clearance and facilitate recovery in an animal model of multiple sclerosis. PLoS Med. 2007;4(4):e124.PubMedPubMedCentralCrossRef
131.
Piccio L, Buonsanti C, Mariani M, Cella M, Gilfillan S, Cross AH, et al. Blockade of TREM-2 exacerbates experimental autoimmune encephalomyelitis. Eur J Immunol. 2007;37(5):1290–301.PubMedCrossRef
132.
Negrotto L, Correale J. Amino acid catabolism in multiple sclerosis affects immune homeostasis. J Immunol. 2017;198(5):1900–9.PubMedCrossRef
133.
Kwidzinski E, Bunse J, Aktas O, Richter D, Mutlu L, Zipp F, et al. Indolamine 2, 3-dioxygenase is expressed in the CNS and down‐regulates autoimmune inflammation. FASEB J. 2005;19(10):1347–9.PubMedCrossRef
134.
Baydyuk M, Cha DS, Hu J, Yamazaki R, Miller EM, Smith VN et al. Tracking the evolution of CNS remyelinating lesion in mice with neutral red dye. Proceedings of the National Academy of Sciences. 2019;116(28):14290-9.
135.
Hu J, Melchor GS, Ladakis D, Reger J, Kim HW, Chamberlain KA, et al. Myeloid cell-associated aromatic amino acid metabolism facilitates CNS myelin regeneration. NPJ Regenerative Med. 2024;9(1):1.CrossRef
136.
Fitzgerald KC, Smith MD, Kim S, Sotirchos ES, Kornberg MD, Douglas M et al. Multi-omic evaluation of metabolic alterations in multiple sclerosis identifies shifts in aromatic amino acid metabolism. Cell Rep Med. 2021;2(10).
137.
van der Poel M, Ulas T, Mizee MR, Hsiao C-C, Miedema SS, Adelia n, et al. Transcriptional profiling of human microglia reveals grey–white matter heterogeneity and multiple sclerosis-associated changes. Nat Commun. 2019;10(1):1139.PubMedPubMedCentralCrossRef
138.
Mehta V, Pei W, Yang G, Li S, Swamy E, Boster A, et al. Iron is a sensitive biomarker for inflammation in multiple sclerosis lesions. PLoS ONE. 2013;8(3):e57573.PubMedPubMedCentralCrossRef
139.
Khalil M, Teunissen C, Langkammer C. Iron and neurodegeneration in multiple sclerosis. Multiple sclerosis international. 2011;2011.
140.
Proto JD, Zhang M, Ryan S, Yao X, Huang Y, Chang Y-C et al. Disrupted microglial iron homeostasis in progressive multiple sclerosis. bioRxiv. 2021:2021.05. 09.443127.
141.
Lee DW, Andersen JK. Role of HIF-1 in iron regulation: potential therapeutic strategy for neurodegenerative disorders. Curr Mol Med. 2006;6(8):883–93.PubMedCrossRef
142.
Rissanen E, Tuisku J, Rokka J, Paavilainen T, Parkkola R, Rinne JO, et al. In vivo detection of diffuse inflammation in secondary progressive multiple sclerosis using PET imaging and the radioligand 11 C-PK11195. J Nucl Med. 2014;55(6):939–44.PubMedCrossRef
143.
Marras C, Beck J, Bower J, Roberts E, Ritz B, Ross G, et al. Prevalence of Parkinson’s disease across North America. NPJ Parkinson’s Disease. 2018;4(1):21.PubMedPubMedCentralCrossRef
144.
145.
Simon DK, Tanner CM, Brundin P. Parkinson disease epidemiology, pathology, genetics, and pathophysiology. Clin Geriatr Med. 2020;36(1):1–12.PubMedCrossRef
146.
Zhu B, Yin D, Zhao H, Zhang L, editors. The immunology of Parkinson’s disease. Seminars in Immunopathology. Springer; 2022.
147.
Lee H-J, Suk J-E, Bae E-J, Lee S-J. Clearance and deposition of extracellular α-synuclein aggregates in microglia. Biochem Biophys Res Commun. 2008;372(3):423–8.PubMedCrossRef
148.
149.
Emmanouilidou E, Melachroinou K, Roumeliotis T, Garbis SD, Ntzouni M, Margaritis LH, et al. Cell-produced α-synuclein is secreted in a calcium-dependent manner by exosomes and impacts neuronal survival. J Neurosci. 2010;30(20):6838–51.PubMedPubMedCentralCrossRef
150.
Danzer KM, Kranich LR, Ruf WP, Cagsal-Getkin O, Winslow AR, Zhu L, et al. Exosomal cell-to-cell transmission of alpha synuclein oligomers. Mol Neurodegeneration. 2012;7:1–18.CrossRef
151.
Bliederhaeuser C, Grozdanov V, Speidel A, Zondler L, Ruf WP, Bayer H, et al. Age-dependent defects of alpha-synuclein oligomer uptake in microglia and monocytes. Acta Neuropathol. 2016;131:379–91.PubMedCrossRef
152.
Zhang W, Phillips K, Wielgus AR, Liu J, Albertini A, Zucca FA, et al. Neuromelanin activates microglia and induces degeneration of dopaminergic neurons: implications for progression of Parkinson’s disease. Neurotox Res. 2011;19:63–72.PubMedCrossRef
153.
Rueda-Carrasco J, Sokolova D, Lee SE, Childs T, Jurčáková N, Crowley G, et al. Microglia‐synapse engulfment via PtdSer‐TREM2 ameliorates neuronal hyperactivity in Alzheimer’s disease models. EMBO J. 2023;42(19):e113246.PubMedPubMedCentralCrossRef
154.
Badanjak K, Fixemer S, Smajić S, Skupin A, Grünewald A. The contribution of microglia to neuroinflammation in Parkinson’s disease. Int J Mol Sci. 2021;22(9):4676.PubMedPubMedCentralCrossRef
155.
Calsolaro V, Edison P. Neuroinflammation in Alzheimer’s disease: current evidence and future directions. Alzheimer’s Dement. 2016;12(6):719–32.CrossRef
156.
Dunn L, Allen GF, Mamais A, Ling H, Li A, Duberley KE, et al. Dysregulation of glucose metabolism is an early event in sporadic Parkinson’s disease. Neurobiol Aging. 2014;35(5):1111–5.PubMedPubMedCentralCrossRef
157.
Edison P, Ahmed I, Fan Z, Hinz R, Gelosa G, Ray Chaudhuri K, et al. Microglia, amyloid, and glucose metabolism in Parkinson’s disease with and without dementia. Neuropsychopharmacology. 2013;38(6):938–49.PubMedPubMedCentralCrossRef
158.
Tai YF, Pavese N, Gerhard A, Tabrizi SJ, Barker RA, Brooks DJ, et al. Imaging microglial activation in Huntington’s disease. Brain Res Bull. 2007;72(2–3):148–51.PubMedCrossRef
159.
Iannaccone S, Cerami C, Alessio M, Garibotto V, Panzacchi A, Olivieri S, et al. In vivo microglia activation in very early dementia with Lewy bodies, comparison with Parkinson’s disease. Parkinsonism Relat Disord. 2013;19(1):47–52.PubMedCrossRef
160.
Qiao H, He X, Zhang Q, Yuan H, Wang D, Li L, et al. Alpha-synuclein induces microglial migration via PKM2-dependent glycolysis. Int J Biol Macromol. 2019;129:601–7.PubMedCrossRef
161.
Stefanis L. α-Synuclein in Parkinson’s disease. Cold Spring Harbor Perspect Med. 2012;2(2):a009399.CrossRef
162.
Rodriguez-Araujo G, Nakagami H, Hayashi H, Mori M, Shiuchi T, Minokoshi Y, et al. Alpha-synuclein elicits glucose uptake and utilization in adipocytes through the Gab1/PI3K/Akt transduction pathway. Cell Mol Life Sci. 2013;70:1123–33.PubMedCrossRef
163.
Lu J, Wang C, Cheng X, Wang R, Yan X, He P, et al. A breakdown in microglial metabolic reprogramming causes internalization dysfunction of α-synuclein in a mouse model of Parkinson’s disease. J Neuroinflamm. 2022;19(1):1–21.CrossRef
164.
Qiao H, He X, Zhang Q, Zhang N, Li L, Hui Y, et al. Α-synuclein induces microglial cell migration through stimulating HIF‐1α accumulation. J Neurosci Res. 2017;95(9):1809–17.PubMedCrossRef
165.
Nakai D, Yuasa S, Takahashi M, Shimizu T, Asaumi S, Isono K, et al. Mouse homologue of coq7/clk-1, longevity gene in Caenorhabditis elegans, is essential for coenzyme Q synthesis, maintenance of mitochondrial integrity, and neurogenesis. Biochem Biophys Res Commun. 2001;289(2):463–71.PubMedCrossRef
166.
Gu R, Zhang F, Chen G, Han C, Liu J, Ren Z, et al. Clk1 deficiency promotes neuroinflammation and subsequent dopaminergic cell death through regulation of microglial metabolic reprogramming. Brain Behav Immun. 2017;60:206–19.PubMedCrossRef
167.
Joshi L, Plastira I, Bernhart E, Reicher H, Koyani CN, Madl T, et al. Lysophosphatidic acid induces aerobic glycolysis, lipogenesis, and increased amino acid uptake in BV-2 microglia. Int J Mol Sci. 2021;22(4):1968.PubMedPubMedCentralCrossRef
168.
Panicker N, Sarkar S, Harischandra DS, Neal M, Kam T-I, Jin H, et al. Fyn kinase regulates misfolded α-synuclein uptake and NLRP3 inflammasome activation in microglia. J Exp Med. 2019;216(6):1411.PubMedPubMedCentralCrossRef
169.
Arab HH, Safar MM, Shahin NN. Targeting ROS-dependent AKT/GSK-3β/NF-κB and DJ-1/Nrf2 pathways by dapagliflozin attenuates neuronal injury and motor dysfunction in rotenone-induced Parkinson’s disease rat model. ACS Chem Neurosci. 2021;12(4):689–703.PubMedCrossRef
170.
Zhou Q, Zhang Y, Lu L, Zhang H, Zhao C, Pu Y, et al. Copper induces microglia-mediated neuroinflammation through ROS/NF-κB pathway and mitophagy disorder. Food Chem Toxicol. 2022;168:113369.PubMedCrossRef
171.
Takeuchi H, Jin S, Wang J, Zhang G, Kawanokuchi J, Kuno R, et al. Tumor necrosis factor-α induces neurotoxicity via glutamate release from hemichannels of activated microglia in an autocrine manner. J Biol Chem. 2006;281(30):21362–8.PubMedCrossRef
172.
Reynolds AD, Kadiu I, Garg SK, Glanzer JG, Nordgren T, Ciborowski P, et al. Nitrated alpha-synuclein and microglial neuroregulatory activities. J Neuroimmune Pharmacol. 2008;3:59–74.PubMedPubMedCentralCrossRef
173.
Bak LK, Schousboe A, Waagepetersen HS. The glutamate/GABA-glutamine cycle: aspects of transport, neurotransmitter homeostasis and ammonia transfer. J Neurochem. 2006;98(3):641–53.PubMedCrossRef
174.
Lind-Holm Mogensen F, Sousa C, Ameli C, Badanjak K, Pereira SL, Muller A, et al. PARK7/DJ-1 deficiency impairs microglial activation in response to LPS-induced inflammation. J Neuroinflamm. 2024;21(1):174.CrossRef
175.
Brekk OR, Honey JR, Lee S, Hallett PJ, Isacson O. Cell type-specific lipid storage changes in Parkinson’s disease patient brains are recapitulated by experimental glycolipid disturbance. Proceedings of the National Academy of Sciences. 2020;117(44):27646-54.
176.
Marschallinger J, Iram T, Zardeneta M, Lee SE, Lehallier B, Haney MS, et al. Lipid-droplet-accumulating microglia represent a dysfunctional and proinflammatory state in the aging brain. Nat Neurosci. 2020;23(2):194–208.PubMedPubMedCentralCrossRef
177.
Loving BA, Tang M, Neal MC, Gorkhali S, Murphy R, Eckel RH, et al. Lipoprotein lipase regulates microglial lipid droplet accumulation. Cells. 2021;10(2):198.PubMedPubMedCentralCrossRef
178.
Illarioshkin S, Klyushnikov S, Vigont V, Seliverstov YA, Kaznacheyeva E. Molecular pathogenesis in Huntington’s disease. Biochem (Moscow). 2018;83:1030–9.CrossRef
179.
180.
181.
Khoshnan A, Ko J, Watkin EE, Paige LA, Reinhart PH, Patterson PH. Activation of the IκB kinase complex and nuclear factor-κB contributes to mutant huntingtin neurotoxicity. J Neurosci. 2004;24(37):7999–8008.PubMedPubMedCentralCrossRef
182.
183.
Schwarcz R, Guidetti P, Sathyasaikumar KV, Muchowski PJ. Of mice, rats and men: revisiting the quinolinic acid hypothesis of Huntington’s disease. Prog Neurobiol. 2010;90(2):230–45.PubMedCrossRef
184.
Palazuelos J, Aguado T, Pazos MR, Julien B, Carrasco C, Resel E, et al. Microglial CB2 cannabinoid receptors are neuroprotective in Huntington’s disease excitotoxicity. Brain. 2009;132(11):3152–64.PubMedCrossRef
185.
Reijonen S, Kukkonen JP, Hyrskyluoto A, Kivinen J, Kairisalo M, Takei N, et al. Downregulation of NF-κB signaling by mutant huntingtin proteins induces oxidative stress and cell death. Cell Mol Life Sci. 2010;67:1929–41.PubMedPubMedCentralCrossRef
186.
Bečanović K, Nørremølle A, Neal SJ, Kay C, Collins JA, Arenillas D, et al. A SNP in the HTT promoter alters NF-κB binding and is a bidirectional genetic modifier of Huntington disease. Nat Neurosci. 2015;18(6):807–16.PubMedCrossRef
187.
Marcora E, Kennedy MB. The Huntington’s disease mutation impairs Huntingtin’s role in the transport of NF-κB from the synapse to the nucleus. Hum Mol Genet. 2010;19(22):4373–84.PubMedPubMedCentralCrossRef
188.
Träger U, Andre R, Lahiri N, Magnusson-Lind A, Weiss A, Grueninger S, et al. HTT-lowering reverses Huntington’s disease immune dysfunction caused by NFκB pathway dysregulation. Brain. 2014;137(3):819–33.PubMedPubMedCentralCrossRef
189.
Reddy V, Grogan D, Ahluwalia M, Salles ÉL, Ahluwalia P, Khodadadi H, et al. Targeting the endocannabinoid system: a predictive, preventive, and personalized medicine-directed approach to the management of brain pathologies. EPMA J. 2020;11:217–50.PubMedPubMedCentralCrossRef
190.
Wang Q, Zhao Y, Sun M, Liu S, Li B, Zhang L, et al. 2-Deoxy-d-glucose attenuates sevoflurane-induced neuroinflammation through nuclear factor-kappa B pathway in vitro. Toxicol in Vitro. 2014;28(7):1183–9.PubMedCrossRef
191.
192.
Giorgini F, Moller T, Kwan W, Zwilling D, Wacker JL, Hong S, et al. Histone deacetylase inhibition modulates kynurenine pathway activation in yeast, microglia, and mice expressing a mutant huntingtin fragment. J Biol Chem. 2008;283(12):7390–400.PubMedCrossRef
193.
Ryu JK, Kim SU, McLarnon JG. Blockade of quinolinic acid-induced neurotoxicity by pyruvate is associated with inhibition of glial activation in a model of Huntington’s disease. Exp Neurol. 2004;187(1):150–9.PubMedCrossRef
194.
Tan Z, Xie N, Cui H, Moellering DR, Abraham E, Thannickal VJ, et al. Pyruvate dehydrogenase kinase 1 participates in macrophage polarization via regulating glucose metabolism. J Immunol. 2015;194(12):6082–9.PubMedCrossRef
195.
Van Bergen JM, Hua J, Unschuld PG, Lim IAL, Jones CK, Margolis RL, et al. Quantitative susceptibility mapping suggests altered brain iron in Premanifest Huntington disease. Am J Neuroradiol. 2016;37(5):789–96.PubMedPubMedCentralCrossRef
196.
Bartzokis G, Cummings J, Perlman S, Hance DB, Mintz J. Increased basal ganglia iron levels in Huntington disease. Arch Neurol. 1999;56(5):569–74.PubMedCrossRef
197.
Simmons DA, Casale M, Alcon B, Pham N, Narayan N, Lynch G. Ferritin accumulation in dystrophic microglia is an early event in the development of Huntington’s disease. Glia. 2007;55(10):1074–84.PubMedCrossRef
198.
González-Guevara E, Cárdenas G, Pérez‐Severiano F, Martínez‐Lazcano JC. Dysregulated brain cholesterol metabolism is linked to neuroinflammation in Huntington’s disease. Mov Disord. 2020;35(7):1113–27.PubMedCrossRef
199.
200.
Rothstein JD. Current hypotheses for the underlying biology of amyotrophic lateral sclerosis. Ann Neurol. 2009;65(S1):S3–9.PubMedCrossRef
201.
Beers DR, Henkel JS, Zhao W, Wang J, Appel SH. CD4 + T cells support glial neuroprotection, slow disease progression, and modify glial morphology in an animal model of inherited ALS. Proceedings of the National Academy of Sciences. 2008;105(40):15558-63.
202.
Philips T, Robberecht W. Neuroinflammation in amyotrophic lateral sclerosis: role of glial activation in motor neuron disease. Lancet Neurol. 2011;10(3):253–63.PubMedCrossRef
203.
Funalot B, Desport J-C, Sturtz F, Camu W, Couratier P. High metabolic level in patients with familial amyotrophic lateral sclerosis. Amyotroph Lateral Scler. 2009;10(2):113–7.PubMedCrossRef
204.
205.
Tefera TW, Borges K. Metabolic dysfunctions in amyotrophic lateral sclerosis pathogenesis and potential metabolic treatments. Front NeuroSci. 2017;10:611.PubMedPubMedCentralCrossRef
206.
Vallée A, Lecarpentier Y, Guillevin R, Vallée J-N. Aerobic glycolysis in amyotrophic lateral sclerosis and Huntington’s disease. Rev Neurosci. 2018;29(5):547–55.PubMedCrossRef
207.
Wiedemann FR, Manfredi G, Mawrin C, Beal MF, Schon EA. Mitochondrial DNA and respiratory chain function in spinal cords of ALS patients. J Neurochem. 2002;80(4):616–25.PubMedCrossRef
208.
Borthwick GM, Johnson MA, Ince PG, Shaw PJ, Turnbull DM. Mitochondrial enzyme activity in amyotrophic lateral sclerosis: implications for the role of mitochondria in neuronal cell death. Annals Neurology: Official J Am Neurol Association Child Neurol Soc. 1999;46(5):787–90.CrossRef
209.
Carrì MT, D’Ambrosi N, Cozzolino M. Pathways to mitochondrial dysfunction in ALS pathogenesis. Biochem Biophys Res Commun. 2017;483(4):1187–93.PubMedCrossRef
210.
Sunyach C, Michaud M, Arnoux T, Bernard-Marissal N, Aebischer J, Latyszenok V, et al. Olesoxime delays muscle denervation, astrogliosis, microglial activation and motoneuron death in an ALS mouse model. Neuropharmacology. 2012;62(7):2346–53.PubMedCrossRef
211.
Niida-Kawaguchi M, Kakita A, Noguchi N, Kazama M, Masui K, Kato Y, et al. Soluble iron accumulation induces microglial glutamate release in the spinal cord of sporadic amyotrophic lateral sclerosis. Neuropathology. 2020;40(2):152–66.PubMedCrossRef
212.
Milanese M, Giribaldi F, Melone M, Bonifacino T, Musante I, Carminati E, et al. Knocking down metabotropic glutamate receptor 1 improves survival and disease progression in the SOD1G93A mouse model of amyotrophic lateral sclerosis. Neurobiol Dis. 2014;64:48–59.PubMedCrossRef
213.
Parone PA, Da Cruz S, Han JS, McAlonis-Downes M, Vetto AP, Lee SK, et al. Enhancing mitochondrial calcium buffering capacity reduces aggregation of misfolded SOD1 and motor neuron cell death without extending survival in mouse models of inherited amyotrophic lateral sclerosis. J Neurosci. 2013;33(11):4657–71.PubMedPubMedCentralCrossRef
214.
Bonifacino T, Cattaneo L, Gallia E, Puliti A, Melone M, Provenzano F, et al. In-vivo effects of knocking-down metabotropic glutamate receptor 5 in the SOD1G93A mouse model of amyotrophic lateral sclerosis. Neuropharmacology. 2017;123:433–45.PubMedCrossRef
215.
Hu Y, Cao K, Wang F, Wu W, Mai W, Qiu L, et al. Dual roles of hexokinase 2 in shaping microglial function by gating glycolytic flux and mitochondrial activity. Nat Metabolism. 2022;4(12):1756–74.CrossRef
216.
Haney MS, Pálovics R, Munson CN, Long C, Johansson PK, Yip O et al. APOE4/4 is linked to damaging lipid droplets in Alzheimer’s disease microglia. Nature. 2024:1–8.
217.
Hopperton KE, Trépanier M-O, Giuliano V, Bazinet RP. Brain omega-3 polyunsaturated fatty acids modulate microglia cell number and morphology in response to intracerebroventricular amyloid-β 1–40 in mice. J Neuroinflamm. 2016;13:1–18.CrossRef
218.
Leng L, Yuan Z, Pan R, Su X, Wang H, Xue J, et al. Microglial hexokinase 2 deficiency increases ATP generation through lipid metabolism leading to β-amyloid clearance. Nat Metabolism. 2022;4(10):1287–305.CrossRef
219.
Gonzalez-Gil A, Porell RN, Fernandes SM, Maenpaa E, Li TA, Li T et al. Human brain sialoglycan ligand for CD33, a microglial inhibitory siglec implicated in Alzheimer’s disease. J Biol Chem. 2022;298(6).
220.
Lin Y-T, Seo J, Gao F, Feldman HM, Wen H-L, Penney J, et al. APOE4 causes widespread molecular and cellular alterations associated with Alzheimer’s disease phenotypes in human iPSC-derived brain cell types. Neuron. 2018;98(6):1141–54. e7.PubMedPubMedCentralCrossRef
221.
Victor MB, Leary N, Luna X, Meharena HS, Scannail AN, Bozzelli PL, et al. Lipid accumulation induced by APOE4 impairs microglial surveillance of neuronal-network activity. Cell Stem Cell. 2022;29(8):1197–212. e8.PubMedPubMedCentralCrossRef
222.
Liu C-C, Wang N, Chen Y, Inoue Y, Shue F, Ren Y, et al. Cell-autonomous effects of APOE4 in restricting microglial response in brain homeostasis and Alzheimer’s disease. Nat Immunol. 2023;24(11):1854–66.PubMedCrossRef
223.
Lee S, Devanney NA, Golden LR, Smith CT, Schwartz JL, Walsh AE et al. APOE modulates microglial immunometabolism in response to age, amyloid pathology, and inflammatory challenge. Cell Rep. 2023;42(3).
224.
Zrzavy T, Hametner S, Wimmer I, Butovsky O, Weiner HL, Lassmann H. Loss of ‘homeostatic’microglia and patterns of their activation in active multiple sclerosis. Brain. 2017;140(7):1900–13.PubMedPubMedCentralCrossRef
225.
Shijie J, Takeuchi H, Yawata I, Harada Y, Sonobe Y, Doi Y, et al. Blockade of glutamate release from microglia attenuates experimental autoimmune encephalomyelitis in mice. Tohoku J Exp Med. 2009;217(2):87–92.PubMedCrossRef
226.
Meng F, Yu W, Duan W, Wang T, Liu Y. Dexmedetomidine attenuates LPS-mediated BV2 microglia cells inflammation via inhibition of glycolysis. Fundam Clin Pharmacol. 2020;34(3):313–20.PubMedCrossRef
227.
Sradhanjali S, Reddy MM. Inhibition of pyruvate dehydrogenase kinase as a therapeutic strategy against Cancer. Curr Top Med Chem. 2018;18(6):444–53.PubMedCrossRef
228.
Ramanan S, Kooshki M, Zhao W, Hsu FC, Riddle DR, Robbins ME. The PPARalpha agonist fenofibrate preserves hippocampal neurogenesis and inhibits microglial activation after whole-brain irradiation. Int J Radiat Oncol Biol Phys. 2009;75(3):870–7.PubMedPubMedCentralCrossRef
229.
Bernardo A, Minghetti L. PPAR-γ Agonists as Regulators of Microglial Activation and Brain Inflammation. Current Pharmaceutical Design. 2006;12(1):93–109.
230.
Carta AR, Pisanu A. Modulating microglia activity with PPAR-γ agonists: a promising therapy for Parkinson’s disease? Neurotox Res. 2013;23(2):112–23.PubMedCrossRef
231.
232.
Vilalta A, Brown GC. Deoxyglucose prevents neurodegeneration in culture by eliminating microglia. J Neuroinflamm. 2014;11:1–10.CrossRef
233.
He D, Xu H, Zhang H, Tang R, Lan Y, Xing R, et al. Disruption of the IL-33-ST2-AKT signaling axis impairs neurodevelopment by inhibiting microglial metabolic adaptation and phagocytic function. Immunity. 2022;55(1):159–73. e9.PubMedPubMedCentralCrossRef
234.
Lauro C, Limatola C. Metabolic reprograming of microglia in the regulation of the innate inflammatory response. Front Immunol. 2020;11:523362.CrossRef
235.
Mikitsh JL, Chacko A-M. Pathways for small molecule delivery to the central nervous system across the blood-brain barrier. Perspect Med Chem. 2014;6:PMC.
Metadata
Title
Fueling neurodegeneration: metabolic insights into microglia functions
Authors
Mohammadamin Sadeghdoust
Aysika Das
Deepak Kumar Kaushik
Publication date
01-12-2024
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2024
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-024-03296-0

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Correction: Glyphosate infiltrates the brain and increases pro-inflammatory cytokine TNFα: implications for neurodegenerative disorders

  • Open Access
  • Correction

iPSC-derived PSEN2 (N141I) astrocytes and microglia exhibit a primed inflammatory phenotype

CB2 expression in mouse brain: from mapping to regulation in microglia under inflammatory conditions

Reimagining the meninges from a neuroimmune perspective: a boundary, but not peripheral

  • Open Access
  • Review

Dimethyl fumarate improves cognitive impairment and neuroinflammation in mice with Alzheimer’s disease

Single-cell RNA sequencing reveals the evolution of the immune landscape during perihematomal edema progression after intracerebral hemorrhage

  • Open Access
  • Edema
  • Original Research
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