Emerging evidence supports the therapeutic potential of cannabinoids in Alzheimer’s disease (AD), but the underlying mechanism upon how cannabinoids impact brain cognition and AD pathology remains unclear. Here we show that chronic cannabidiol (CBD) administration significantly mitigates cognitive deficiency and hippocampal β-amyloid (Aβ) pathology in 5×FAD mouse model of AD. CBD achieves its curative effect mainly through potentiating the function of inhibitory extrasynaptic glycine receptor (GlyR) in hippocampal dentate gyrus (DG). Based on the in vitro and in vivo electrophysiological recording and calcium imaging, CBD mediated anti-AD effects via GlyR are mainly accomplished by decreasing neuronal hyperactivity of granule cells in the DG of AD mice. Furthermore, the AAV-mediated ablation of DG GlyRα1, or the GlyRα1^S296A mutation that exclusively disrupts CBD binding, significantly intercepts the anti-AD effect of CBD. These findings suggest a GlyR dependent mechanism underlying the therapeutic potential of CBD in the treatment of AD.

新出现的证据支持大麻素在阿尔茨海默病 （AD） 中的治疗潜力，但大麻素如何影响大脑认知和 AD 病理学的潜在机制仍不清楚。在这里，我们表明，在 AD 的 5×FAD 小鼠模型中，慢性大麻二酚 （CBD） 给药显着减轻了认知缺陷和海马 β-淀粉样蛋白 （Aβ） 病理学。CBD 主要通过增强海马齿状回 （DG） 中抑制性突触外甘氨酸受体 （GlyR） 的功能来实现其疗效。基于体外和体内电生理记录和钙成像，CBD 通过 GlyR 介导的抗 AD 作用主要是通过减少 AD 小鼠 DG 中颗粒细胞的神经元过度活动来实现的。此外，AAV 介导的 DG GlyRα1 消融，或仅破坏 CBD 结合的 GlyRα1^S296A 突变，显着拦截了 CBD 的抗 AD 作用。这些发现表明，CBD治疗AD的治疗潜力存在GlyR依赖机制。