Sanz-Blasco Sara, Piña-Crespo Juan C, Zhang Xiaofei, McKercher Scott R, Lipton Stuart A
aNeurodegenerative Disease Center, Scintillon Institute bDepartment of Neurosciences, School of Medicine, University of California, San Diego cDel E. Webb Center for Neuroscience, Aging and Stem Cell Research, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA.
Neuroreport. 2016 Jun 15;27(9):705-9. doi: 10.1097/WNR.0000000000000601.
A recently identified mechanism for oligomeric Aβ-induced glutamate release from astrocytes involves intracellular Ca elevation, potentially by Ca-dependent vesicular release. Evidence suggests that levetiracetam (LEV; Keppra), an antiepileptic drug, can improve cognitive performance in both humans with mild cognitive impairment and animal models of Alzheimer disease. Because LEV acts by modulating neurotransmitter release from neurons by interaction with synaptic vesicles, we tested the effect of LEV on Aβ-induced astrocytic release of glutamate. We used a fluorescence resonance energy transfer-based glutamate sensor (termed SuperGluSnFR), whose structure is based on the ligand-binding site of glutamate receptors, to monitor glutamate release from primary cultures of human astrocytes exposed to oligomeric amyloid-β peptide 1-42 (Aβ42). We found that LEV (10 µM) inhibited oligomeric Aβ-induced astrocytic glutamate release. In addition, we show that this Aβ-induced glutamate release from astrocytes is sensitive to tetanus neurotoxin, an inhibitor of the vesicle release machinery. Taken together, our evidence suggests that LEV inhibits Aβ-induced vesicular glutamate release from astrocytes and thus may underlie, at least in part, the ability of LEV to reduce hyperexcitability in Alzheimer disease.
最近发现的一种机制表明，低聚Aβ诱导星形胶质细胞释放谷氨酸涉及细胞内钙升高，这可能是通过钙依赖性囊泡释放实现的。有证据表明，抗癫痫药物左乙拉西坦（LEV；开浦兰）可以改善轻度认知障碍患者和阿尔茨海默病动物模型的认知表现。由于左乙拉西坦通过与突触囊泡相互作用来调节神经元释放神经递质，我们测试了左乙拉西坦对Aβ诱导的星形胶质细胞释放谷氨酸的影响。我们使用了一种基于荧光共振能量转移的谷氨酸传感器（称为SuperGluSnFR），其结构基于谷氨酸受体的配体结合位点，来监测暴露于低聚淀粉样β肽1-42（Aβ42）的人星形胶质细胞原代培养物中谷氨酸的释放。我们发现左乙拉西坦（10µM）抑制了低聚Aβ诱导的星形胶质细胞谷氨酸释放。此外，我们表明，这种Aβ诱导的星形胶质细胞谷氨酸释放对破伤风神经毒素敏感，破伤风神经毒素是囊泡释放机制的抑制剂。综上所述，我们的证据表明左乙拉西坦抑制Aβ诱导的星形胶质细胞囊泡谷氨酸释放，因此至少部分地可能是左乙拉西坦降低阿尔茨海默病中过度兴奋能力的基础。
