Abstract
Neuroinflammation is recognised as a common feature of the pathological disease process in a number of chronic neurodegenerative conditions including Alzheimer’s disease, Parkinson’s disease, multiple sclerosis and Huntington’s disease. In recent years, the endocannabinoid system has been implicated in disease pathogenesis, with putative roles in many of these neurological conditions. In the present study, Huntington’s disease was utilised as a model in which the neuroinflammatory response and the pattern of CB2 receptor expression was investigated in both the human condition and R6/1 transgenic mouse model.
In the human brain, consistent with previous evidence, a significant increase in the level of astrocytic immune cells was noted with increasing pathological grade. Microglial cell number was significantly increased in grade 1 HD, but was seen to decrease at later pathological stages of disease. Significant morphological changes to both immune cell types were also noted in later disease grades. In the present study, CB2 receptors were demonstrated to colocalise on endothelial cells in the blood vessel wall, in contrast with previous evidence suggesting localisation of these receptors on microglial immune cells. This lack of microglial CB2 expression is thought to be attributed to a difference in the activation state of microglia in the HD brain, as compared to that in other neurodegenerative conditions.
The findings of the animal study showed that at 20 weeks of age, R6/1 mice do not demonstrate an inflammatory response. Few significant differences in microglial cell levels were noted in R6/1 mice as compared to WT littermates in both drug-treated cohorts. In addition, a lack of astrocyte expression seen in the striatum of these animals supported the lack of an immune response. CB2 receptor expression was not detected in R6/1 mice at 20 weeks of age. However, evidence to support CB2 expression at later stages of disease in the R6/1 model suggest that the time point at which these mice were investigated precedes the age at which CB2 may be reliably detected. As such, further investigation into the pathological disease process in these animals may be required. Alternatively, it is likely that an animal model better suited to reflect the pathology seen in the human condition be employed to further study Huntington’s disease.
Whilst in the present study cannabinoid drug treatment did not produce any effects on immune cell expression in R6/1 mice, other animal models of Huntington’s disease have demonstrated the potential of cannabinoid compounds in attenuating disease symptomatology. Further investigation into the localisation and role of CB2 receptors in the human Huntington’s disease brain may allow for the potential of these drugs to be translated to the human condition.