Inhibition of tumour necrosis factor alpha in the R6/2 mouse model of Huntington's disease by etanercept treatment

Huntington's disease (HD) is an inherited neurodegenerative disorder caused by the expansion of the CAG repeat in exon 1 of the huntingtin (HTT) gene, which results in a mutant protein with an extended polyglutamine tract. Inflammation occurs in both the brain and the periphery of HD patients and mouse models, with increases in brain and/or plasma levels of neurotoxicTNF alpha and several other proinflammatory cytokines.TNF alpha promotes the generation of many of these cytokines, such as IL6, which raises the possibility that TNF alpha is central to the inflammatory milieu associated with HD. A number of mouse studies have reported that the suppression of chronic immune activation during HD has beneficial consequences. Here, we investigated whether TNF alpha contributes to the peripheral inflammation that occurs in the R6/2 mouse model, and whether the in vivo blockade of TNF alpha, via etanercept treatment, can modify disease progression. We found that etanercept treatment normalised the elevated plasma levels of some cytokines. This did not modify the progression of certain behavioural measures, but slightly ameliorated brain weight loss, possibly related to a reduction in the elevated striatal level of soluble TNF alpha.