PT  - JOURNAL ARTICLE
AU  - Jill Bouchard
AU  - Jennifer Truong
AU  - Kristofer Bouchard
AU  - Diana Dunkelberger
AU  - Sandrine Desrayaud
AU  - Saliha Moussaoui
AU  - Sarah J. Tabrizi
AU  - Nephi Stella
AU  - Paul J. Muchowski
TI  - Cannabinoid Receptor 2 Signaling in Peripheral Immune Cells Modulates Disease Onset and Severity in Mouse Models of Huntington's Disease
AID  - 10.1523/JNEUROSCI.4008-12.2012
DP  - 2012 Dec 12
TA  - The Journal of Neuroscience
PG  - 18259--18268
VI  - 32
IP  - 50
4099  - http://www.jneurosci.org/content/32/50/18259.short
4100  - http://www.jneurosci.org/content/32/50/18259.full
SO  - J. Neurosci.2012 Dec 12; 32
AB  - Peripheral immune cells and brain microglia exhibit an activated phenotype in premanifest Huntington's disease (HD) patients that persists chronically and correlates with clinical measures of neurodegeneration. However, whether activation of the immune system contributes to neurodegeneration in HD, or is a consequence thereof, remains unclear. Signaling through cannabinoid receptor 2 (CB2) dampens immune activation. Here, we show that the genetic deletion of CB2 receptors in a slowly progressing HD mouse model accelerates the onset of motor deficits and increases their severity. Treatment of mice with a CB2 receptor agonist extends life span and suppresses motor deficits, synapse loss, and CNS inflammation, while a peripherally restricted CB2 receptor antagonist blocks these effects. CB2 receptors regulate blood interleukin-6 (IL-6) levels, and IL-6 neutralizing antibodies partially rescue motor deficits and weight loss in HD mice. These findings support a causal link between CB2 receptor signaling in peripheral immune cells and the onset and severity of neurodegeneration in HD, and they provide a novel therapeutic approach to treat HD.