Activation of Wnt signaling promotes hippocampal neurogenesis in experimental autoimmune encephalomyelitis. Issue 1 (December 2016)

• Record Type: Journal Article
• Authors: Schneider, Reiner; Koop, Barbara; Schröter, Friederike; Cline, Jason; Ingwersen, Jens; Berndt, Carsten; Hartung, Hans-Peter; Aktas, Orhan; Prozorovski, Tim
• Is Part Of: Molecular neurodegeneration. Volume 11:Issue 1(2016)
• Page Start: 1
• Page End: 16
• Publication Date: 2016-12
• Subjects: Wnt -- Hippocampus -- Neurogenesis -- EAE -- Multiple sclerosis; Neurobiology -- Periodicals; Nervous system -- Diseases -- Periodicals; 616.8
• DOI: 10.1186/s13024-016-0117-0
• Languages: English
• ISSNs: 1750-1326

Abstract

Abstract Background 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. Results In the present study, we used theWnt signaling reporter mouse Axin2LacZ, 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 hippocampalWnt /β-catenin activity, one of the key signaling pathways of adult neurogenesis. We found thatWnt signaling is transiently upregulated in the acute stage of disease, consistent with a timely induction of canonicalWnt 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 theWnt /β-catenin pathway. Supporting this finding, we show that transient exposure to pro-inflammatory cytokine TNFα triggersWnt signaling in hippocampal organotypic slice cultures. Importantly, inflammation-mediated activation of theWnt /β-catenin pathway was associated with enhanced neurogenesis in vitro and in vivo, indicating its potential role in hippocampal tissue regeneration and repair. Conclusions This study raises the possibility that enhancement ofWnt signaling may support neurogenic processes to cope with neuronal deficits upon immune-mediated neuroinflammation.