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Antje Diestel¹, Orhan Aktas², Dagmar Hackel¹, Ines Häke¹, Susanne Meier², Cedric S. Raine³, Robert Nitsch¹, Frauke Zipp² and Oliver Ullrich^1,4

¹ Department of Cell and Neurobiology, Institute of Anatomy
² Institute of Neuroimmunology, Clinical and Experimental Neuroimmunology, University Hospital Charité, 10098 Berlin, Germany
³ Albert Einstein College of Medicine, New York, NY 10461
⁴ Institute of Immunology, University Hospital Magdeburg, 39120 Magdeburg, Germany

Address correspondence to Oliver Ullrich, Department of Cell and Neurobiology, Institute of Anatomy, Medical Faculty Charité, Humboldt-University Berlin, Philippstr. 12, 10115 Berlin, Germany. Phone: 49-30-450-528245; Fax: 49-30-450-528300; email: oliver.ullrich{at}charite.de

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.

Key Words: multiple sclerosis • glia • neurodegeneration • encephalomyelitis • integrins

R. Nitsch, F. Zipp, and O. Ullrich contributed equally to this work.

Abbreviations used in this paper: BHT, ß-hydroxytoluol; CNS, central nervous system; CSF, cerebrospinal fluid; DTT, dithiothreitol; EAE, experimental autoimmune encephalomyelitis; GC/MS, gas chromatography/mass spectrometry; HPLC, high performance liquid chromatography; ICAM, intercellular adhesion molecule; iNOS, inducible nitric oxide synthase; MS, multiple sclerosis; NF, nuclear factor; OHSC, organotypic hippocampal slice culture; OND, other neurological disease; PARP, poly(ADP-ribose)-polymerase; w.w., wet weight.

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