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Hum Mol Genet. 2014 Aug 15;23(16):4328-44. doi: 10.1093/hmg/ddu151. Epub 2014 Apr 3.

Inhibition of soluble tumor necrosis factor is therapeutic in Huntington's disease.

Author information

1
Institute of Biomedical Sciences Institute of Neuroscience, National Yang-Ming University, Taipei, Taiwan.
2
Institute of Cellular and Organismic Biology and.
3
Department of Neurology, Chang Gung Memorial Hospital, Linkou Medical Center and College of Medicine, Chang-Gung University, Taoyuan, Taiwan.
4
Institute of Biomedical Sciences.
5
Institute of Cellular and Organismic Biology and Genomics Research Center, Academia Sinica, Taipei 115, Taiwan.
6
Institute of Biomedical Sciences Institute of Neuroscience, National Yang-Ming University, Taipei, Taiwan bmychern@ibms.sinica.edu.tw.

Abstract

Neuroinflammation is a common feature of many neurodegenerative diseases, including Huntington's disease (HD). HD is an autosomal dominant genetic disease caused by an expanded CAG repeat in exon 1 of the huntingtin (HTT) gene. Previous studies demonstrated that levels of several proinflammatory cytokines, including tumor necrosis factor (TNF)-α, were higher in the plasma and brain tissues of mice and patients with HD, suggesting that inflammation may contribute to HD progression. To evaluate the pathological role of TNF-α in HD pathogenesis, we blocked TNF-α signaling using a dominant negative inhibitor of soluble TNF-α (XPro1595). XPro1595 effectively suppressed the inflammatory responses of primary astrocytes-enriched culture isolated from a transgenic mouse model (R6/2) and human astrocytes-enriched culture derived from induced pluripotent stem cells (iPSCs) of HD patients evoked by lipopolysaccharide and cytokines, respectively. Moreover, XPro1595 protected the cytokine-induced toxicity of primary R6/2 neurons and human neurons derived from iPSCs of HD patients. To assess the beneficial effect of XPro1595 in vivo, an intracerebroventricular (i.c.v.) infusion was provided with an osmotic minipump. ELISA analyses showed that i.c.v. infusion of XPro1595 decreased elevated levels of TNFα in the cortex and striatum, improved motor function, reduced caspase activation, diminished the amount of mutant HTT aggregates, increased neuronal density and decreased gliosis in brains of R6/2 mice. Moreover, reducing the peripheral inflammatory response by a systemic injection of XPro1595 improved the impaired motor function of R6/2 mice but did not affect caspase activation. Collectively, our findings suggest that an effective and selective anti-inflammatory treatment targeting the abnormal brain inflammatory response is a potential therapeutic strategy for HD.

PMID:
24698979
DOI:
10.1093/hmg/ddu151
[Indexed for MEDLINE]

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