鸟苷神经保护用β-淀粉样蛋白寡聚体进行的小鼠研究中的突触前线粒体钙稳态

Guanosine neuroprotection of presynaptic mitochondrial calcium homeostasis in a mouse study with amyloid-β oligomers.

Keywords：Alzheimer’s disease, Amyloid-β oligomers, Guanosine, Neuroprotection, Presynaptic mitochondria 

关键词：阿尔茨海默病、β-淀粉样蛋白寡聚体、鸟苷、神经保护、突触前线粒体 
作者：Souza da Silva Jussemara , Nonose Yasmine , Rohden Francieli , Lukasewicz Ferreira Pamela C , Fontella Fernanda Urruth , Rocha Andreia , Wigner Brochier Andressa , Vieira Apel Rodrigo , de Lima Thais Martins , Seminotti Bianca , Umpierrez Amaral Alexandre , Galina Antonio , Souza Diogo O
出版期刊：《Mol Neurobiol》（2020/8/13）

Abstract：

Amyloid-β oligomers (AβOs) toxicity causes mitochondrial dysfunction, leading to synaptic failure in Alzheimer's disease (AD). Considering presynaptic high energy demand and tight Ca2+ regulation, impairment of mitochondrial function can lead to deteriorated neural activity and cell death. In this study, an AD mouse model induced by ICV (intracerebroventricular) injection of AβOs was used to investigate the toxicity of AβOs on presynaptic function. As a therapeutic approach, GUO (guanosine) was given by oral route to evaluate the neuroprotective effects on this AD model. Following 24 h and 48 h from the model induction, behavioral tasks and biochemical analyses were performed, respectively. AβOs impaired object recognition (OR) short-term memory and reduced glutamate uptake and oxidation in the hippocampus. Moreover, AβOs decreased spare respiratory capacity, reduced ATP levels, impaired Ca2+ handling, and caused mitochondrial swelling in hippocampal synaptosomes. Guanosine crossed the BBB, recovered OR short-term memory, reestablished glutamate uptake, recovered mitochondrial Ca2+ homeostasis, and partially prevented mitochondrial swelling. Therefore, this endogenous purine presented a neuroprotective effect on presynaptic mitochondria and should be considered for further studies in AD models.

文章摘要：

β-淀粉样蛋白寡聚体 (AβOs) 的毒性会导致线粒体功能障碍，从而导致阿尔茨海默病 (AD) 的突触功能障碍。考虑到突触前的高能量需求和严格的 Ca2+ 调节，线粒体功能受损会导致神经活动恶化和细胞死亡。在本研究中，通过 ICV（脑室内）注射 AβOs 诱导的 AD 小鼠模型用于研究 AβOs 对突触前功能的毒性。作为一种治疗方法，通过口服途径给予GUO（鸟苷）以评估对该AD模型的神经保护作用。在模型诱导 24 小时和 48 小时后，分别进行行为任务和生化分析。AβOs 损害对象识别 (OR) 短期记忆并减少海马中谷氨酸的摄取和氧化。而且，AβOs 降低了备用呼吸能力，降低了 ATP 水平，损害了 Ca2+ 处理，并导致海马突触体中的线粒体肿胀。鸟苷穿过血脑屏障，恢复或短期记忆，重新建立谷氨酸摄取，恢复线粒体 Ca2+ 稳态，并部分防止线粒体肿胀。因此，这种内源性嘌呤对突触前线粒体具有神经保护作用，应考虑在 AD 模型中进行进一步研究。

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