CB2 receptor agonist improves memory performance in Alzheimer's disease mouse models

Assistant Professor Akira Sobue and Professor Koji Yamanaka of the Research Institute of Environmental Medicine and Graduate School of Medicine at Nagoya University in Japan have reported a potential new treatment for Alzheimer’s disease (AD). Their findings, published in Cell Death and Disease, demonstrate that stimulating CB2 using JWH 133 improved cognitive function in AD mouse models. The study was conducted in collaboration with researchers from Nagoya City University, Tokyo Metropolitan Geriatric Hospital, and RIKEN. 

CB2 is integral to the endocannabinoid system, which regulates various physiological processes, including the immune response, inflammation, pain, and neuronal signaling. The research team found that CB2 is predominantly expressed in microglia cells and its expression levels increase as AD progresses. This pattern appeared in both AD mouse models and human brain tissue samples. 

“In immunology research, agonists are commonly used to activate receptors in the body to investigate their effects. However, they are less often examined in neurological disease research, such as AD studies,” Yamanaka said. “We were interested in using JWH 133, a CB2 receptor agonist, to conduct AD behavioral studies.”  

The researchers used mice running mazes and performing recognition tasks to assess cognitive function. They found that JWH 133 significantly improved the decline in object recognition memory and spatial memory in AD mice.  

"These discoveries suggest CB2 is a therapeutic target for AD and potentially other neurodegenerative diseases," Yamanaka said. 

Further investigation revealed that CB2 activation reduced the release of complement C1q, a protein that regulates inflammation. Although complement C1q typically controls inflammation by regulating inflammatory cells called astrocytes, it triggers an excessive inflammatory response in patients with AD, leading to the neuroinflammation that is characteristic of the disease. 

“The number of dementia patients in Japan is projected to reach 6 million by 2040; however, the current antibody-based drugs are limited by high costs and restricted patient eligibility, emphasizing the importance of alternative approaches,” Yamanaka said. “We found that CB2 stimulation mitigates harmful neuroinflammation while promoting a neuroprotective environment. This approach provides a more cost-effective alternative to existing drugs and potentially expands treatment eligibility for a greater number of patients.”