The role of cannabinoid receptor 2 in microglial clearance of human tau.

Abstract

It is well accepted that neuroinflammation is a key component in the pathobiology of Alzheimer's disease (AD). Multiple studies have demonstrated a strong neuroinflammatory response in the presence of Tau pathology, which is strongly associated with the clinical symptoms and cognitive decline found in AD patients. The correlation between AD progression and tau pathologies, rather than Ab accumulation, suggests that targeting pathological tau may be a more effective therapeutic approach. Microglia have been implicated in tauopathies as they may contribute to tau phosphorylation and aggregation and the uptake and spread of seed-competent tau to healthy neurons due to dysfunctional degradation. Cannabinoid type 2 receptors (CB2) are highly expressed in immune cells and upregulated in activated microglia under conditions of neurologic disease, such as AD. Moreover, the pharmacological modulation of CB2 using CB2-selective compounds have demonstrated a reduction in inflammation and plaque deposition, suggesting a role of CB2 on the immune system to influence AD-related pathologies and phenotypes. However, there are limited findings on the CB2 regulation of tau accumulation. Brain slice cultures will be generated from CB2-EGFP knock-in mice and transduced with virus-mediated tau previously shown to accumulate total tau and develop insoluble tau species. Brain slices will be evaluated for tau pathology and microglial phenotypes using real-time imaging and biochemical analyses. Previous investigation in our lab of a synucleinopathy animal model revealed the capacity of CB2 to alter the function of immune cells and reduce accumulation of toxic human alpha-synuclein. Furthermore, we have determined that treatment with a CB2 inverse agonist will increase phagocytosis of pHrodo E. coli bioparticles in microglia BV2 cultures stimulated by LPS. We are currently working with brain slice cultures to evaluate how CB2 alters the behavior of microglia including phagocytosis and clearance of human tau. These studies will advance our understanding of the role of CB2 in the microglial contribution to pathologic tau removal and potentially highlight CB2 as a therapeutic target against tauopathies such as AD.