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

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.

Systems-Level G Protein-Coupled Receptor Therapy Across a Neurodegenerative Continuum by the GLP-1 Receptor System

“…In addition to altered chemokine profiles, there is considerable evidence that demonstrates increased levels of circulating and CNS-borne pro-inflammatory cytokines, including IL-6, IL-8, and TNF-α (147). Reinforcing the potential importance of TNF-α in HD pathogenesis, it has recently been shown that therapeutic inhibition of TNF-α activity can significantly attenuate central and peripheral inflammation in the R6/2 HD model mice (149). …”

The choreography of neuroinflammation in Huntington's disease

“…R6/2 astrocytes also produced more damage on primary R6/2 neurons in comparison to control astrocytes during inflammation in vitro . The role of TNFα in HD pathogenesis was examined using the dominant negative inhibitor XPro1595 [82]. XPro1595 is a selective inhibitor of soluble TNFα that interferes with its binding to TNFα receptors.…”

Neuroimmunology of Huntington’s Disease: Revisiting Evidence from Human Studies

“…Moreover, XPro1595 protected the cytokine-induced toxicity in both in vitro models. In vivo , XPro1595 decreased TNF- α levels 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 the brain of R6/2 mice [58]. …”