School of Precision Instrument and Opto-Electronics Engineering, Tianjin University, Tianjin, 300072, People's Republic of China.
State Key Laboratory of Cognitive Neuroscience and Learning & IDG/McGovern Institute for Brain Research, Beijing Normal University, Beijing, 100875, People's Republic of China.
Neuromolecular Med. 2017 Sep;19(2-3):423-435. doi: 10.1007/s12017-017-8458-6. Epub 2017 Aug 1.
Chronic cerebral hypoperfusion (CCH) is associated with various neurodegenerative diseases characterized by cognitive impairment. Dozens of studies including ours have indicated that exogenous administration of vascular endothelial growth factor (VEGF) could exert effective cognitive protection during ischemia. Nevertheless, the underlying mechanism has not been well clarified. To address this issue, we explored the synaptic mechanisms in vivo since hippocampal synaptic function is essential to the learning and memory process. Besides, the role of autophagy in cognitive dysfunction under conditions of CCH is still controversial. And abnormal autophagy could threaten normal neurotransmission at synapse where a large amount of protein synthesis and degradation take place. Hence, we further examined whether the altered synaptic function was associated with autophagy. The results showed that CCH impaired spatial cognition as evidenced in Morris water maze. We further found that VEGF mitigated impaired hippocampal synaptic function including basal synaptic transmission, paired-pulse facilitation, short-term, long-term plasticity, depotentiation, and the level of synaptic proteins as assessed by electrophysiological examination and western blot assay. Furthermore, our results demonstrated that CCH could induce excessive autophagy which could be inhibited by VEGF. Thus, we speculated that VEGF could ameliorate impaired synaptic function induced by CCH because of its ability to inhibit excessive autophagy, and eventually improve spatial learning and memory function. Importantly, our findings shed light on potential therapeutic strategies to be exploited in the usage of VEGF.
慢性脑灌注不足（CCH）与各种以认知障碍为特征的神经退行性疾病有关。包括我们在内的数十项研究表明，外源性给予血管内皮生长因子（VEGF）在缺血期间可发挥有效的认知保护作用。然而，其潜在机制尚未得到充分阐明。为了解决这个问题，我们在体内探索了突触机制，因为海马突触功能对于学习和记忆过程至关重要。此外，自噬在 CCH 条件下认知功能障碍中的作用仍存在争议。异常的自噬可能会威胁到突触处正常的神经递质传递，因为突触处有大量的蛋白质合成和降解。因此，我们进一步研究了改变的突触功能是否与自噬有关。结果表明，CCH 损害了空间认知，这在 Morris 水迷宫中得到了证明。我们进一步发现，VEGF 减轻了海马突触功能的损伤，包括基础突触传递、成对脉冲易化、短期、长期可塑性、去极化和突触蛋白水平，这是通过电生理检查和 Western blot 分析评估的。此外，我们的结果表明，CCH 可诱导过度自噬，而 VEGF 可抑制过度自噬。因此，我们推测 VEGF 可以改善 CCH 引起的受损突触功能，因为它具有抑制过度自噬的能力，最终改善空间学习和记忆功能。重要的是，我们的发现为利用 VEGF 提供了潜在的治疗策略。
