大麻抑制β淀粉样多肽导致的星形胶质细胞半通道激活:一种神经元保护机制

Cannabinoids prevent the amyloid-induced activation of astroglial hemichannels:A neuroprotectivemechanism

阿尔茨海默病(AD)的机制尚不完全清楚,星形胶质细胞及其信号传导在AD中的作用也有待进一步研究。既往研究表明,β淀粉样多肽(Aβ)会导致神经元死亡,其可能的机制为Aβ导致星形胶质细胞半通道开放,并由此增加兴奋性毒性ATP和谷氨酸释放。本课题组的既往研究显示,激活的小胶质细胞或炎症介质可导致星形胶质细胞上缝隙连接43半通道开放;而外源性或内源性大麻均可以减少这种开放。但尚不清楚大麻是否可以减少由Aβ激活星形胶质细胞半通道导致的神经元死亡。本研究培养星形胶质细胞及海马脑片,分别单用Aβ处理或用Aβ及大麻(WIN,2-AG,或甲酰胺基)联合处理。采用单通道膜片钳及延时乙啡啶摄取法记录胶质细胞半通道的活动,采用Fluoro-Jade C染色检测神经元死亡。结果显示,大麻完全抑制了由Aβ导致的星形胶质细胞半通道的活性及炎症反应。而且,大麻完全抑制了由Aβ导致的星形胶质细胞缝隙连接43半通道开放而引起的兴奋毒性谷氨酸及ATP的释放,大麻也可以很大程度上减少由Aβ导致的海马脑片神经元的损伤。通过调节星形胶质细胞的功能来保护神经元是目前治疗AD的新策略,本研究结果为此提供了新思路。

The mechanisms involved in Alzheimer＇s disease are not completely understood and how astrocytes and their gliotransmission contribute to this neurodegenerative disease remains to be fully elucidated. Previous studies have shown that amyloid-β peptide （Aβ） induces neuronal death by a mechanism that involves the excitotoxic release of ATP and glutamate associated to astroglialhemichannel opening. We have demonstrated that synthetic and endogenous cannabinoids （CBs） reduce the opening of astrocyte Cx43 hemichannels evoked by activated microglia or inflammatory mediators. Nevertheless, whether CBs could prevent the astroglialhemichannel-dependent death of neurons evoked by Aβ is unknown. Astrocytes as well as acute hippocampal slices were treated with the active fragment of Aβ alone or in combination with the following CBs： WIN, 2-AG, or methanandamide （Meth）. Hemichannel activity was monitored by single channel recordings and by time-lapse ethidium uptake while neuronal death was assessed by Fluoro-Jade C staining. We report that CBs fully prevented the hemichannel activity and inflammatory profile evoked by Aβ in astrocytes. Moreover, CBs fully abolished the Aβ-induced release of excitotoxic glutamate and ATP associated to astroeyte Cx43 hemichannel activity, as well as neuronal damage in hippocampal slices exposed to Aβ. Consequently, this work opens novel avenues for alternative treatments that target astrocytes to maintain neuronal function and survival during AD.