Jin Jin, Fu Chonglei, Xia Jing, Luo Heyi, Wang Xianglian, Chen Si, Mao Huanhuan, Yuan Kai, Lu Lin, Xiong Wei, Zou Guichang
Department of neurology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230026, China.
Institute of Brain Science and Brain-inspired Research, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, 250117, China.
Mol Psychiatry. 2025 May;30(5):1817-1827. doi: 10.1038/s41380-024-02789-x. Epub 2024 Oct 12.
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 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）治疗中的潜力，但大麻素如何影响大脑认知和AD病理的潜在机制仍不清楚。在这里，我们表明，在5×FAD AD小鼠模型中，长期给予大麻二酚（CBD）可显著减轻认知缺陷和海马β-淀粉样蛋白（Aβ）病理。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）的功能来实现其治疗效果。基于体外和体内电生理记录以及钙成像，CBD通过GlyR介导的抗AD作用主要是通过降低AD小鼠DG中颗粒细胞的神经元过度活动来实现的。此外，腺相关病毒介导的DG GlyRα1缺失，或仅破坏CBD结合的GlyRα1突变，显著阻断了CBD的抗AD作用。这些发现表明，CBD治疗AD的潜在机制依赖于GlyR。
