title: Activation of microglial poly(ADP-ribose)-polymerase-1 by cholesterol breakdown products during neuroinflammation: a link between demyelination and neuronal damage.
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.
authors.affiliation: Department of Cell and Neurobiology, Institute of Anatomy, University Hospital Charité, Berlin, Germany.
authors.forename: Antje
authors.initials: A
authors.lastname: Diestel
authors.forename: Orhan
authors.initials: O
authors.lastname: Aktas
authors.forename: Dagmar
authors.initials: D
authors.lastname: Hackel
authors.forename: Ines
authors.initials: I
authors.lastname: Hake
authors.forename: Susanne
authors.initials: S
authors.lastname: Meier
authors.forename: Cedric S
authors.initials: CS
authors.lastname: Raine
authors.forename: Robert
authors.initials: R
authors.lastname: Nitsch
authors.forename: Frauke
authors.initials: F
authors.lastname: Zipp
authors.forename: Oliver
authors.initials: O
authors.lastname: Ullrich
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D004789:Enzyme Activation; D006801:Humans; D007653:Ketocholesterols / Q000134:cerebrospinal fluid; D051379:Mice; D017628:Microglia / Q000201:enzymology*; D009103:Multiple Sclerosis / Q000134:cerebrospinal fluid / Q000201:enzymology* / Q000473:pathology; D009474:Neurons / Q000473:pathology*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*
chemical_list: D007653:Ketocholesterols; D002784:Cholesterol; D011065:Poly(ADP-ribose) Polymerases; C003001:7-ketocholesterol