缺乏N-cadherin-Akt3信号破坏了血脑屏障
Quinn Lee1, Wan Ching Chan1, Shuangping Zhao1
1Department of Pharmacology and Regenerative Medicine, University of Illinois College of Medicine, Chicago, IL 60612, USA.
Cell reports
|June 12, 2025
概括
衰老通过降低N-cadherin来破坏血脑屏障 (BBB),这会破坏奥克卢丁紧接点 (TJ) 的稳定. 这导致大脑功能受损和记忆力缺陷.
科学领域:
- 神经科学是一个神经科学.
- 细胞生物学 细胞生物学
- 血管生物学 血管生物学
背景情况:
- 血脑屏障 (BBB) 通过通过大脑内皮细胞 (BEC) 之间的紧密连接 (TJ) 调节对细胞运输来维持大脑平衡.
- 与年龄相关的BBB完整性下降是一个重大问题,但推动这一过程的分子机制尚未完全理解.
- 在BECs和 pericytes之间通过N-cadherin介导的细胞粘附对于BBB功能至关重要.
研究的目的:
- 调查N-cadherin在与年龄相关的BBB功能障碍中的作用.
- 阐明N-cadherin影响TJ稳定性和BBB完整性的分子机制.
主要方法:
- 来自年轻和中年患者的人类皮质组织的分析.
- 在内皮细胞 (ECs) 中对N-cadherin的遗传操纵.
- 评估奥克卢丁TJ定位,大脑输液和空间记忆.
主要成果:
- 与年龄相关的血管N-cadherin损失与人类大脑组织中奥克卢丁TJ干扰相关.
- 在EC中N-cadherin的遗传删除导致了受损的奥克卢丁TJs,大脑输液减少和空间记忆缺陷.
- N-cadherin通过氨基酸3-激酶p110β-Akt3信号通路稳定了奥克卢丁TJs,这种信号通路随着年龄的增长而受损. 奥克卢丁Ser471向Ala的突变也破坏了TJs的稳定.
结论:
- N-cadherin 作为一个关键的信号枢纽,通过以酸化依赖的方式在TJs稳定奥克卢丁来维持BBB完整性.
- 干扰N-cadherin介导的信号通路有助于与年龄相关的BBB分解.
- 准N-cadherin介导的信号可能提供治疗策略,以对抗与年龄相关的认知衰退和BBB功能障碍.
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