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

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  • Antje Diestel
    1Department of Cell and Neurobiology, Institute of Anatomy
  • Orhan Aktas
    2Institute of Neuroimmunology, Clinical and Experimental Neuroimmunology, University Hospital Charité, 10098 Berlin, Germany
  • Dagmar Hackel
    1Department of Cell and Neurobiology, Institute of Anatomy
  • Ines Häke
    1Department of Cell and Neurobiology, Institute of Anatomy
  • Susanne Meier
    2Institute of Neuroimmunology, Clinical and Experimental Neuroimmunology, University Hospital Charité, 10098 Berlin, Germany
  • Cedric S. Raine
    3Albert Einstein College of Medicine, New York, NY 10461
  • Robert Nitsch
    1Department of Cell and Neurobiology, Institute of Anatomy
  • Frauke Zipp
    2Institute of Neuroimmunology, Clinical and Experimental Neuroimmunology, University Hospital Charité, 10098 Berlin, Germany
  • Oliver Ullrich
    1Department of Cell and Neurobiology, Institute of Anatomy

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<jats:p>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.</jats:p>

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