Liu DianWei, Zheng Yan, Chen Yuan, Jiang Yang, Wang HuiYun, Li LingMei, Ma Ling
Department of Stroke Center, Central Hospital Affiliated to Shandong First Medical University, Jinan, People's Republic of China.
Department of Stroke Center, Jinan Central Hospital, Cheeloo College of Medicine, Shandong University, Jinan, People's Republic of China.
J Neurochem. 2023 May;165(4):587-602. doi: 10.1111/jnc.15808. Epub 2023 Mar 31.
Ischemic stroke triggers a cascade of events that facilitates neural protection and spontaneous recovery, which accounts for a major part of functional recovery. Despite the cellular and molecular facilitations on neural protection, the molecular mechanisms of spontaneous recovery have not been fully understood. Ca -dependent activator protein for secretion 1 (CAPS1), a member of CAPS family, plays a major role in synaptic transmission and synaptic effectiveness by regulating vesicle exocytosis. Here, the molecular mechanism of CAPS1 in spontaneous recovery after ischemic stroke was studied. In this study, transient left middle cerebral artery occlusion (MCAO) was used as the ischemic stroke model. The whole brain magnetic resonance imaging (MRI) and neurological score analysis showed decreased infarct volume and neurological scores at 7 days as compared with 1 day after MCAO, suggesting the spontaneous recovery. Elisa and Western blot analysis showed elevated BDNF and CAPS1 expression levels in bilateral hippocampus at both 1 day and 3 days after MCAO. Then, inhibition of CAPS1 by adeno-associated virus (AAV) microinjection in the hippocampus attenuated the spontaneous recovery of both motor and memory impairment induced by MCAO. In addition, elevated p-TrkB levels were detected after MCAO, which were reduced by CAPS1-AAV microinjection, indicating that CAPS1 could induce BDNF secretion after ischemic stroke. Moreover, we found elevated combination of CAPS1 with dense core vesicles (DCV) in the hippocampus at both 1 day and 3 days after MCAO, which could also be inhibited by CAPS1-AAV microinjection, indicating the potential mechanism of CAPS1 in regulating BDNF release after MCAO. Finally, we found that CAPS1/BDNF signaling could influence the neurogenesis in the hippocampus after MCAO. In conclusion, CAPS1 regulates neurogenesis by up-regulating BDNF release in the hippocampus, which finally facilitate spontaneous recovery after ischemic stroke.
缺血性中风引发一系列有助于神经保护和自发恢复的事件，这是功能恢复的主要部分。尽管在神经保护方面有细胞和分子层面的促进作用，但自发恢复的分子机制尚未完全明确。分泌型钙依赖性激活蛋白1（CAPS1）是CAPS家族的一员，通过调节囊泡胞吐作用在突触传递和突触效能中发挥主要作用。在此，对CAPS1在缺血性中风后自发恢复中的分子机制进行了研究。在本研究中，采用短暂性大脑中动脉闭塞（MCAO）作为缺血性中风模型。全脑磁共振成像（MRI）和神经学评分分析显示，与MCAO后1天相比，MCAO后7天时梗死体积和神经学评分降低，提示自发恢复。酶联免疫吸附测定（ELISA）和蛋白质印迹分析显示，MCAO后1天和3天双侧海马中脑源性神经营养因子（BDNF）和CAPS1的表达水平均升高。然后，通过在海马中显微注射腺相关病毒（AAV）抑制CAPS1，减弱了MCAO诱导的运动和记忆障碍的自发恢复。此外，MCAO后检测到磷酸化酪氨酸激酶受体B（p-TrkB）水平升高，而CAPS1-AAV显微注射可使其降低，表明CAPS1可在缺血性中风后诱导BDNF分泌。此外，我们发现MCAO后1天和3天海马中CAPS1与致密核心囊泡（DCV）的结合增加，CAPS1-AAV显微注射也可抑制这种结合，这表明CAPS1在MCAO后调节BDNF释放的潜在机制。最后，我们发现CAPS1/BDNF信号通路可影响MCAO后海马中的神经发生。总之，CAPS1通过上调海马中BDNF的释放来调节神经发生，最终促进缺血性中风后的自发恢复。
