Remote ischemic conditioning alleviates chronic cerebral hypoperfusion-induced cognitive decline and synaptic dysfunction via the miR-218a-5p/SHANK2 pathway
Remote ischemic conditioning alleviates chronic cerebral hypoperfusion-induced cognitive decline and synaptic dysfunction via the miR-218a-5p/SHANK2 pathway
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DOI：
10.1016/j.pneurobio.2023.102514
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发表时间：
2023-08-28
影响因子：
6.7
通讯作者：
Ji，Xuming
中科院分区：
文献类型：
--
作者：
Li，Ning;Ren，Changhong;Ji，Xuming
血管性认知功能障碍（VCI）是由慢性脑灌注不足（CCH）引起的，是痴呆的第二大原因。虽然突触损伤在VCI中起着关键作用，但其确切机制仍不清楚。我们前期的研究表明，远程缺血性条件反射（RIC）可以减轻慢性脑缺血引起的认知功能下降，但其对突触损伤的影响尚不清楚。在这项研究中，我们证实，RIC缓解了由CCH引起的认知下降及其相关的突触功能障碍。RNA测序显示，CCH增加了miR-218 a-5 p的表达，而RIC降低了该表达。升高的miR-218 a-5 p水平限制了RIC的益处，然而，抑制海马CA 1神经元中的miR-218 a-5 p挽救了突触功能障碍。此外，我们发现SHANK 2是miR-218 a-5 p的下游靶标，并且抑制SHANK 2表达减少了由缺氧条件化引起的体外突触损伤的缓解。总之，我们的研究结果表明，RIC通过miR-218 a-5 p/SHANK 2通路减轻突触损伤，这可能是CCH引起的认知障碍的潜在生物标志物或治疗靶点。
Vascular cognitive impairment (VCI) due to chronic cerebral hypoperfusion (CCH), is the second leading cause of dementia. Although synaptic impairment plays a critical role in VCI, its exact mechanism remains unknown. Our previous research revealed that remote ischemic conditioning (RIC) could alleviate cognitive decline resulting from CCH, however, its effects on synaptic impairment remain unclear. In this study, we confirmed that RIC alleviated both cognitive decline and its associated synaptic dysfunction caused by CCH. RNA sequencing revealed that CCH increased in miR-218a-5p expression, which was decreased by RIC. Elevated miR-218a-5p levels limited the benefits of RIC, however, inhibiting miR-218a-5p in hippocampal CA1 neurons rescued synaptic dysfunction. Additionally, we found that SHANK2 is a downstream target of miR-218a-5p, and inhibiting SHANK2 expression reduced the alleviation caused by hypoxic conditioning in synaptic impairment in vitro. In conclusion, our results suggested that RIC alleviated synaptic impairment via the miR-218a-5p/SHANK2 pathway, which could be a potential biomarker or therapeutic target for cognitive impairment caused by CCH.