Department of Neurology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, 301 Middle Yanchang Road, Shanghai, 200072, China.
J Nanobiotechnology. 2021 Oct 15;19(1):324. doi: 10.1186/s12951-021-01070-5.
The ratio of excitatory to inhibitory neurotransmitters is essential for maintaining the firing patterns of neural networks, and is strictly regulated within individual neurons and brain regions. Excitatory to inhibitory (E/I) imbalance has been shown to participate in the progression of neurodegenerative diseases, including Alzheimer's disease (AD). Glutamate excitotoxicity and GABAergic neuron dysfunction appear to be key components of the neuronal cell death that takes place in AD. Since extracellular vesicles (EVs) are now explored as an important vehicle in transmitting signals between cells, we hypothesized that the function of neuron-derived small EVs (sEVs) might be regulated by the status of neurotransmitter balance and that sEVs might affect amyloid β (Aβ) toxicity on neurons. This study aimed to reveal the effects of sEVs from unbalanced neurotransmitter-stimulated neurons on Aβ-induced toxicity. We demonstrated the opposite effects of the two groups of sEVs isolated from neurons stimulated by glutamate or GABA on Aβ toxicity in vivo and in vitro. The sEVs released from GABA-treated neurons alleviated Aβ-induced damage, while those released from glutamate-treated neurons aggravated Aβ toxicity. Furthermore, we compared the microRNA (miRNA) composition of sEVs isolated from glutamate/GABA/PBS-treated neurons. Our results showed that glutamate and GABA oppositely regulated miR-132 levels in sEVs, resulting in the opposite destiny of recipient cells challenged with Aβ. Our results indicated that manipulating the function of sEVs by different neurotransmitters may reveal the mechanisms underlying the pathogenesis of AD and provide a promising strategy for AD treatment.
兴奋性神经递质与抑制性神经递质的比例对于维持神经网络的发射模式至关重要，并且在单个神经元和脑区中受到严格调节。兴奋性神经递质与抑制性神经递质失衡已被证明参与了神经退行性疾病的进展，包括阿尔茨海默病（AD）。谷氨酸兴奋性毒性和 GABA 能神经元功能障碍似乎是 AD 中神经元细胞死亡的关键组成部分。由于细胞外囊泡（EVs）现在被探索作为细胞间传递信号的重要载体，我们假设神经元来源的小 EVs（sEVs）的功能可能受到神经递质平衡状态的调节，并且 sEVs 可能影响神经元上的淀粉样蛋白 β（Aβ）毒性。本研究旨在揭示不平衡神经递质刺激神经元产生的 sEVs 对 Aβ 诱导毒性的影响。我们证明了从谷氨酸或 GABA 刺激的神经元中分离的两组 sEVs 在体内和体外对 Aβ毒性的相反作用。来自 GABA 处理神经元释放的 sEVs 减轻了 Aβ诱导的损伤，而来自谷氨酸处理神经元释放的 sEVs 加重了 Aβ毒性。此外，我们比较了从谷氨酸/ GABA / PBS 处理神经元中分离的 sEVs 的 microRNA（miRNA）组成。我们的结果表明，谷氨酸和 GABA 以相反的方式调节 sEVs 中的 miR-132 水平，导致接受 Aβ挑战的受体细胞的命运相反。我们的结果表明，通过不同的神经递质来操纵 sEVs 的功能可能揭示 AD 发病机制的机制，并为 AD 的治疗提供有希望的策略。
