Cannabinoid receptor type 2 (CB2R) (CB2R)

Cannabinoid receptor type 2 (CB2R) is a G protein-coupled receptor primarily expressed in immune cells, including microglia in the central nervous system (UniProt: P34972). While its expression is low in the healthy brain, it is significantly upregulated in response to neuroinflammation and is found concentrated around amyloid-beta (Aβ) plaques in Alzheimer's disease (PubMed: 22300105). The 'microglial Aβ clearance axis' describes the pathway where CB2R activation triggers signaling cascades that enhance the phagocytic capacity of microglia, allowing them to more effectively engulf and degrade neurotoxic Aβ aggregates (PubMed: 30654024). This activation also shifts microglia from a pro-inflammatory (M1-like) to an anti-inflammatory (M2-like) state, reducing the release of neurotoxic cytokines. Selective CB2R agonists are being investigated as therapeutic agents to promote plaque clearance and neuroprotection without the psychoactive effects associated with the CB1 receptor (PubChem: CID 10430171). However, achieving high selectivity and sufficient blood-brain barrier penetration remains a key challenge in drug development for this target.

Other names

CNR2CB2Cannabinoid receptor 2G protein-coupled receptor 67GPR67

Agonism of the Cannabinoid receptor type 2 (CB2R) activates Gi/o protein signaling, which inhibits adenylyl cyclase and modulates MAPK and PI3K/Akt pathways. In microglia, this signaling promotes a transition to a phagocytic phenotype, increasing the expression of Aβ-degrading enzymes and phagocytic receptors, thereby facilitating the clearance of amyloid-beta plaques (PubMed: 22300105, 30654024).