title: Activation of Wnt signaling promotes hippocampal neurogenesis in experimental autoimmune encephalomyelitis.
abstract: Disease progression in multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE), as one of its animal models, is characterized by demyelination and neuronal damage in white and gray matter structures, including the hippocampus. It is thought that dysfunction of the hippocampus, a primary locus of learning and memory consolidation, may contribute to cognitive impairment in MS patients. Previously, we reported an increased generation of hippocampal neuronal progenitors in the acute stage of EAE, whereas the microenvironmental signals triggering this process remained uninvestigated.
  
  
  
  In the present study, we used the Wnt signaling reporter mouse Axin2(LacZ), to elucidate the molecular mechanisms underlying the activation of the hippocampal neurogenic niche upon autoimmune neuroinflammation. Histological and enzymatic examinations of β-gal during the disease course of EAE, allowed us to survey hippocampal Wnt/β-catenin activity, one of the key signaling pathways of adult neurogenesis. We found that Wnt signaling is transiently upregulated in the acute stage of disease, consistent with a timely induction of canonical Wnt ligands. The enhancement of signaling coincided with hippocampal neuronal damage and local expression of immune cytokines such as TNFα and IFNγ, implicating the role of the inflammatory milieu in activation of the Wnt/β-catenin pathway. Supporting this finding, we show that transient exposure to pro-inflammatory cytokine TNFα triggers Wnt signaling in hippocampal organotypic slice cultures. Importantly, inflammation-mediated activation of the Wnt/β-catenin pathway was associated with enhanced neurogenesis in vitro and in vivo, indicating its potential role in hippocampal tissue regeneration and repair.
  
  
  
  This study raises the possibility that enhancement of Wnt signaling may support neurogenic processes to cope with neuronal deficits upon immune-mediated neuroinflammation.
authors.affiliation: Department of Neurology, Medical Faculty, Heinrich-Heine-University Düsseldorf, Merowingerplatz 1a, Moorenstr.5, 40225, Düsseldorf, Germany.
authors.forename: Reiner
authors.initials: R
authors.lastname: Schneider
authors.affiliation: Department of Neurology, Medical Faculty, Heinrich-Heine-University Düsseldorf, Merowingerplatz 1a, Moorenstr.5, 40225, Düsseldorf, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Koop
authors.affiliation: Department of Neurology, Medical Faculty, Heinrich-Heine-University Düsseldorf, Merowingerplatz 1a, Moorenstr.5, 40225, Düsseldorf, Germany.|Present address: Institute for Stem Cell Research and Regenerative Medicine, Medical Faculty, Heinrich-Heine-University Düsseldorf, Moorenstr. 5, 40225, Düsseldorf, Germany.
authors.forename: Friederike
authors.initials: F
authors.lastname: Schröter
authors.affiliation: Department of Neurology, Medical Faculty, Heinrich-Heine-University Düsseldorf, Merowingerplatz 1a, Moorenstr.5, 40225, Düsseldorf, Germany.
authors.forename: Jason
authors.initials: J
authors.lastname: Cline
authors.affiliation: Department of Neurology, Medical Faculty, Heinrich-Heine-University Düsseldorf, Merowingerplatz 1a, Moorenstr.5, 40225, Düsseldorf, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Ingwersen
authors.affiliation: Department of Neurology, Medical Faculty, Heinrich-Heine-University Düsseldorf, Merowingerplatz 1a, Moorenstr.5, 40225, Düsseldorf, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Berndt
authors.affiliation: Department of Neurology, Medical Faculty, Heinrich-Heine-University Düsseldorf, Merowingerplatz 1a, Moorenstr.5, 40225, Düsseldorf, Germany.
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Hartung
authors.affiliation: Department of Neurology, Medical Faculty, Heinrich-Heine-University Düsseldorf, Merowingerplatz 1a, Moorenstr.5, 40225, Düsseldorf, Germany. orhan.aktas@uni-duesseldorf.de.
authors.forename: Orhan
authors.initials: O
authors.lastname: Aktas
authors.affiliation: Department of Neurology, Medical Faculty, Heinrich-Heine-University Düsseldorf, Merowingerplatz 1a, Moorenstr.5, 40225, Düsseldorf, Germany. Timur.Prozorovskiy@med.uni-duesseldorf.de.
authors.forename: Tim
authors.initials: T
authors.lastname: Prozorovski
mesh_terms: D000818:Animals; D003072:Cognition Disorders / Q000378:metabolism / Q000473:pathology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000378:metabolism*; D005260:Female; D006624:Hippocampus / Q000378:metabolism*; D051379:Mice; D009103:Multiple Sclerosis / Q000378:metabolism; D055495:Neurogenesis / Q000502:physiology*; D060449:Wnt Signaling Pathway / Q000502:physiology*; D051176:beta Catenin / Q000378:metabolism
chemical_list: C495267:CTNNB1 protein, mouse; D051176:beta Catenin
keywords: EAE; Hippocampus; Multiple sclerosis; Neurogenesis; Wnt