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Cited by 155Neuroinflammation and Neurodegeneration MechanismsMultiple Sclerosis Research StudiesNeurological Disease Mechanisms and Treatments

Activation of Microglial Poly(ADP-Ribose)-Polymerase-1 by Cholesterol Breakdown Products during Neuroinflammation

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Diestel, Antje, Aktas, Orhan, Hackel, Dagmar, Häke, Ines, Meier, Susanne, Raine, Cedric S., Nitsch, Robert, Zipp, Frauke +1 more·2003·The Journal of Experimental Medicine
DOI 10.1084/jem.20030975PMC PMC2194134
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Abstract

Multiple sclerosis (MS) is a chronic demyelinating disease in which it has only recently been suggested that damage to neuronal structures plays a key role. Here, we uncovered a link between the release of lipid breakdown products, found in the brain and cerebrospinal fluid (CSF) of MS patients as well as in experimental autoimmune encephalomyelitis, and neuronal damage mediated by microglial activation. The concentrations of the breakdown product 7-ketocholesterol detected in the CSF of MS patients were capable of inducing neuronal damage via the activation and migration of microglial cells in living brain tissue. 7-ketocholesterol rapidly entered the nucleus and activated poly(ADP-ribose)-polymerase (PARP)-1, followed by the expression of migration-regulating integrins CD11a and intercellular adhesion molecule 1. These findings reveal a novel mechanism linking demyelination and progressive neuronal damage, which might represent an underlying insidious process driving disease beyond a primary white matter phenomenon and rendering the microglial PARP-1 a possible antiinflammatory therapeutic target.

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  • Metabolic derangements of cholesterol lead to microglial activation, chronic inflammation, and progression of neurodegenerative diseases.

    “For example, metabolic derangements of cholesterol lead to microglial activation, chronic inflammation, and progression of NDs [65,66].”

    From Lipoprotein Lipase Regulates Microglial Lipid Droplet Accumulation (2021) · cites this paper as [65]

    The Discussion (page not supplied) reports that the cholesterol breakdown product 7-ketocholesterol activates microglia and may sustain neuronal damage and secondary inflammatory cascades in multiple sclerosis. The claim extends this proposed mechanism to cholesterol metabolic derangements and the progression of neurodegenerative diseases generally, which this paper does not establish. (LLM, conf=0.87)

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References 49 · Cited by 155

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  1. [2]Pitt, D., P. Werner, and C.S. Raine. 2000. Glutamate excitotoxicity in a model of multiple sclerosis. Nat. Med. 6: 67–70. 10613826
  2. [3]Smith, T., A. Groom, B. Zhu, and L. Turski. 2000. Autoimmune encephalomyelitis ameliorated by AMPA antagonists. Nat. Med. 6: 62–66. 10613825
  3. [4]Kornek, B., M.K. Storck, R. Weissert, E. Wallstroe, A. Stefferl, T. Olsson, C. Linington, M. Schmidbauer, and H. Lassmann. 2000. Multiple sclerosis and chronic autoimmune encephalomyelitis: a comparative quantitative study of axonal injury in active, inactive, and remyelinated lesions. Am. J. Pathol. 157: 267–276. 10880396 PMC1850217
  4. [6]Ferguson, B., M.K. Matyszak, M.M. Esiri, and V.H. Perry. 1997. Axonal damage in acute multiple sclerosis lesions. Brain. 120: 393–399. 9126051
  5. [7]Coles, A.J., M.G. Wing, P. Molyneux, A. Paolillo, C.M. Davie, G. Hale, D. Miller, H. Waldmann, and A. Compston. 1999. Monoclonal antibody treatment exposes three mechanisms underlying the clinical course of multiple sclerosis. Ann. Neurol. 46: 296–304. 10482259
  6. [8]Bjartmar, C., R.P. Kinkel, G. Kidd, R.A. Rudick, and B.D. Trapp. 2001. Axonal loss in normal-appearing white matter in a patient with acute MS. Neurology. 57: 1248–1252. 11591844
  7. [9]Bjartmar, C., and B.D. Trapp. 2001. Axonal and neuronal degeneration in multiple sclerosis: mechanisms and functional consequences. Curr. Opin. Neurol. 14: 271–278. 11371748
  8. [10]Bjartmar, C., G. Kidd, S. Mork, R. Rudick, and B.D. Trapp. 2000. Neurological disability correlates with spinal cord axonal loss and reduced N-acetyl aspartate in chronic multiple sclerosis patients. Ann. Neurol. 48: 893–901. 11117546
  9. [11]Hemmer, B., J.J. Archelos, and H.-P. Hartung. 2002. New concepts in the immunopathogenesis of multiple sclerosis. Nat. Rev. Neurosci. 3: 291–301. 11967559
  10. [12]Smith, K.J., R. Kapoor, and P.A. Felts. 1999. Demyelination: the role of reactive oxygen and nitrogen species. Brain Pathol. 9: 69–92. 9989453 PMC7161906
  11. [13]Bongarzone, E.R., J.M. Pasquini, and E.F. Soto. 1995. Oxidative damage to proteins and lipids of CNS myelin produced by in vitro generated reactive oxygen species. J. Neurosci. Res. 41: 213–221. 7650757
  12. [14]Lizard, G., M. Moisant, C. Cordelet, S. Monier, P. Gambert, and L. Lagrost. 1997. Induction of similar features of apoptosis in human and bovine vascular endothelial cells treated by 7-ketocholesterol. J. Pathol. 183: 330–338. 9422990
  13. [15]Lizard, G., V. Deckert, L. Dubrez, M. Moisant, P. Gambert, and L. Lagrost. 1996. Induction of apoptosis in endothelial cells treated with cholesterol oxides. Am. J. Pathol. 148: 1625–1638. 8623930 PMC1861569
  14. [16]Zhou, Q., E. Wasowicz, B. Handler, L. Fleischer, and F.A. Kummerow. 2000. An excess concentration of oxysterols in the plasma is cytotoxic to cultured endothelial cells. Atherosclerosis. 149: 191–197. 10704631
  15. [17]Chang, J.Y., and L.Z. Liu. 1998. Neurotoxicity of cholesterol oxides on cultured cerebellar granule cells. Neurochem. Int. 32: 317–323. 9596554
  16. [18]Chang, J.Y., K.D. Phelan, and J.A. Chavis. 1998. Neurotoxicity of 25-OH-cholesterol on sympathetic neurons. Brain Res. Bull. 45: 615–622. 9566506
  17. [19]Chang, J.Y., K.D. Phelan, and L.Z. Liu. 1998. Neurotoxicity of 25-OH-cholesterol on NGF-differentiated PC12 cells. Neurochem. Res. 23: 7–16. 9482261
  18. [20]Poser, C.M., D.W. Paty, L. Scheinberg, W.I. McDonald, F.A. Davis, G.C. Ebers, K.P. Johnson, W.A. Sibley, D.H. Silberberg, and W.W. Tourtellotte. 1983. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann. Neurol. 13: 227–231. 6847134
  19. [21]Raine, C.S. 1997. Demyelinating diseases. Textbook of Neuropathology (Third Edition). R.L. Davis, and D.M. Robertson, editors. Williams and Wilkins, Baltimore. 243–286.
  20. [22]Sevanian, A., R. Seraglia, P. Traldi, P. Rossato, F. Ursini, and H. Hodis. 1994. Analysis of plasma cholesterol oxidation products using gas- and high-performance liquid chromatography/mass spectrometry. Free Radic. Biol. Med. 17: 397–409. 7835746
  21. [23]Kritharides, L., W. Jessup, J. Gifford, and R.T. Dean. 1993. A method for defining the stages of low-density lipoprotein oxidation by the separation of cholesterol- and cholesteryl ester-oxidation products using HPLC. Anal. Biochem. 213: 79–89. 8238886
  22. [24]Raine, C.S. 1984. Biology of disease. The analysis of autoimmune demyelination: its impact upon multiple sclerosis. Lab. Invest. 50: 608–635. 6202955
  23. [25]Brocke, S., A. Gaur, C. Piercy, A. Gautam, K. Gijbels, C.G. Fathman, and L. Steinman. 1993. Induction of relapsing paralysis in experimental autoimmune encephalomyelitis by bacterial superantigen. Nature. 365: 642–644. 7692305
  24. [26]Bocchini, V., R. Mazzolla, R. Barluzzi, E. Blasi, P. Sick, and H. Kettenmann. 1992. An immortalized cell line expresses properties of activated microglial cells. J. Neurosci. Res. 31: 616–621. 1578513
  25. [27]Ullrich, O., A. Diestel, I.Y. Eyüpoglu, and R. Nitsch. 2001. Regulation of microglial expression of integrins by poly(ADP-ribose)polymerase-1. Nat. Cell Biol. 3: 1035–1042. 11781564
  26. [28]Emig, S., D. Schmalz, M. Shakibaei, and K. Buchner. 1995. The nuclear pore complex protein p62 is one of several sialic acid-containing proteins of the nuclear envelope. J. Biol. Chem. 270: 13787–13793. 7775435
  27. [29]Hailer, N.P., J.D. Jarhult, and R. Nitsch. 1996. Resting microglia cells in vitro: analysis of morphology and adhesion molecule expression in organotypic hippocampal slice cultures. Glia. 18: 319–331. 8972800
  28. [30]Murakami, H., N. Tamasawa, J. Matsui, M. Yasujima, and T. Suda. 2000. Plasma oxysterols and tocopherol in patients with diabetes mellitus and hyperlipidemia. Lipids. 35: 333–338. 10783011
  29. [31]Dzeletovic, S., O. Breuer, E. Lund, and U. Diczfalusy. 1995. Determination of cholesterol oxidation products in human plasma by isotope dilution mass-spectrometry. Anal. Biochem. 225: 73–80. 7778789
  30. [32]Dyer, R.G., M.W. Stewart, J. Mitcheson, K. George, M.M. Alberti, and M.F. Laker. 1997. 7-Ketocholesterol, a specific indicator of lipoprotein oxidation, and malonaldehyde in non-insulin dependent diabetes and peripheral vascular disease. Clin. Chim. Acta. 260: 1–13. 9101096
  31. [33]Addis, P.B., H.A. Emanuel, S.D. Bergmann, and J.H. Zayoral. 1989. Capillary GC quantification of cholesterol oxidation products in plasma lipoproteins of fasted humans. Free Radic. Biol. Med. 7: 179–182. 2806942
  32. [34]Posse de Chaves, E.I., D.E. Vance, R.B. Campenot, R.D. Kiss, and J.E. Vance. 2000. Uptake of lipoproteins for axonal growth of sympathetic neurons. J. Biol. Chem. 275: 19883–19890. 10867025
  33. [35]Bondy, S.C., and D.K. Lee. 1993. Oxidative stress induced by glutamate receptor agonists. Brain Res. 610: 229–233. 8319085
  34. [36]Maor, I., M. Kaplan, T. Hayek, J. Vaya, A. Hoffman, and M. Aviram. 2000. Oxidized monocyte-derived macrophages in aortic atherosclerotic lesion from apolipoprotein E-deficient mice and from human carotid artery contain lipid peroxides and oxysterols. Biochem. Biophys. Res. Commun. 269: 775–780. 10720491
  35. [37]Mattson, M.P., S.W. Barger, J.G. Begley, and R.J. Mark. 1995. Calcium, free radicals, and excitotoxic neuronal death in primary cell culture. Methods Cell Biol. 46: 187–216. 7541884
  36. [38]Braun, J.S., R. Novak, K.H. Herzog, S.M. Bodner, J.L. Cleveland, and E.I. Tuomanen. 1999. Neuroprotection by a caspase inhibitor in acute bacterial meningitis. Nat. Med. 5: 298–302. 10086385
  37. [39]Miller, S.D., and W.J. Karpus. 1994. The immunopathogenesis and regulation of T cell-mediated demyelinating diseases. Immunol. Today. 15: 356–361. 7916948
  38. [40]Zamvil, S.S., and L. Steinman. 1990. The T lymphocyte in experimental allergic encephalomyelitis. Annu. Rev. Immunol. 8: 579–621. 2188675
  39. [41]Martin, R., H.F. McFarland, and D.E. McFarlin. 1992. Immunological aspects of demyelinating diseases. Annu. Rev. Immunol. 10: 153–187. 1375472
  40. [42]Noseworthy, J.H., C.F. Lucchinetti, M. Rodriguez, and B.G. Weinshenker. 2000. Multiple sclerosis. N. Engl. J. Med. 343: 938–952. 11006371
  41. [43]Goverman, J., and T. Brabb. 1996. Rodent models of experimental allergic encephalomyelitis applied to the study of multiple sclerosis. Lab. Anim. Sci. 46: 482–492. 8905579
  42. [44]Chang, J.Y., J.A. Chavis, L.Z. Liu, and P.D. Drew. 1998. Cholesterol oxides induce programmed cell death in microglial cells. Biochem. Biophys. Res. Commun. 249: 817–821. 9731219
  43. [45]Chiarugi, A., and M.A. Moskowitz. 2003. Poly(ADP-ribose) polymerase-1 activity promotes NF-kappaB-driven transcription and microglial activation: implication for neurodegenerative disorders. J. Neurochem. 85: 306–317. 12675907
  44. [46]Hassa, P.O., and M.O. Hottiger. 2002. The functional role of poly(ADP-ribose)polymerase-1 as novel coactivator of NF-kappaB in inflammatory disorders. Cell. Mol. Life Sci. 59: 1534–1553. 12440774 PMC11337477
  45. [47]Hassa, P.O., M. Covic, S. Hasan, R. Imhof, and M.O. Hottiger. 2001. The enzymatic and DNA binding activity of PARP-1 are not required for NF-kappaB coactivator function. J. Biol. Chem. 276: 45588–45597. 11590148

Authors
Diestel, A., Aktas, O., Hackel, D., Häke, I., Meier, S., Raine, C. S., Nitsch, R., Zipp, F., & Ullrich, O.
Affiliations
  • Anatomische Anstalt (DE)
  • 2Institute of Neuroimmunology, Clinical and Experimental Neuroimmunology, University Hospital Charité, 10098 Berlin, Germany
  • 1Department of Cell and Neurobiology, Institute of Anatomy
  • Charité – Universitätsmedizin Berlin (DE)
  • Albert Einstein College of Medicine (US)
  • University Hospital Magdeburg (DE)
Corresponding author
Ullrich, Oliver
ORCID
Venue
The Journal of Experimental Medicine
Publisher
Rockefeller University Press
Published
2003-12-01
Volume
198
Issue
11
Pages
1729-1740
ISSN
  • 0022-1007 (ISSN-L)
  • 1540-9538
DOI
10.1084/jem.20030975
PMC
PMC2194134
OpenAlex
W2127426061
Cited by
155
References
49
Citations by year
2026: 7 · 2025: 4 · 2024: 5 · 2023: 5 · 2022: 2 · 2021: 6 · 2020: 6 · 2019: 7 · 2018: 5 · 2017: 4 · 2016: 4 · 2015: 4 · 2014: 6 · 2013: 11 · 2012: 2
FWCI
6.19
Type
journal article
Language
en
Open access
Locations
  • The Journal of Experimental Medicine (publishedVersion)
  • PubMed Central (publishedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
Funders
  • University of Miami
  • Deutsche Forschungsgemeinschaft
  • Bundesministerium für Bildung und Forschung
  • Gemeinnützige Hertie-Stiftung
  • National Institutes of Health
  • National Institute of Mental Health (R24MH059724)
  • National Institute of Neurological Disorders and Stroke (NS-08952, NS-11920, P50NS011920, R01NS008952)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
  • Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
Keywords
multiple sclerosis, microglial activation, PARP1, 7-ketocholesterol, neuroinflammation, neuronal injury, demyelination, experimental autoimmune encephalomyelitis, cerebrospinal fluid, microglial migration, CD11a, ICAM-1, integrins
MeSH terms
Animals, Brain, Cells, Cultured, Cholesterol, Enzyme Activation, Humans, Ketocholesterols, Multiple Sclerosis, Neurons, Poly(ADP-ribose) Polymerases, Microglia, Mice

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