Park Gyeongah, Jin Zhen, Lu Hui, Du Jianyang
Department of Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
Brain Sci. 2024 Dec 10;14(12):1239. doi: 10.3390/brainsci14121239.
Astrocytes, vital support cells in the central nervous system (CNS), are crucial for maintaining neuronal health. In neurodegenerative diseases such as Alzheimer's disease (AD), astrocytes play a key role in clearing toxic amyloid-β (Aβ) peptides. Aβ, a potent neuroinflammatory trigger, stimulates astrocytes to release excessive glutamate and inflammatory factors, exacerbating neuronal dysfunction and death. Recent studies underscore the role of Rho GTPases-particularly RhoA, Rac1, and Cdc42-in regulating Aβ clearance and neuroinflammation. These key regulators of cytoskeletal dynamics and intracellular signaling pathways function independently through distinct mechanisms but may converge to modulate inflammatory responses. Their influence on astrocyte structure and function extends to regulating endothelin-converting enzyme (ECE) activity, which modulates vasoactive peptides such as endothelin-1 (ET-1). Through these processes, Rho GTPases impact vascular permeability and neuroinflammation, contributing to AD pathogenesis by affecting both Aβ clearance and cerebrovascular interactions. Understanding the interplay between Rho GTPases and the cerebrovascular system provides fresh insights into AD pathogenesis. Targeting Rho GTPase signaling pathways in astrocytes could offer a promising therapeutic approach to mitigate neuroinflammation, enhance Aβ clearance, and slow disease progression, ultimately improving cognitive outcomes in AD patients.
星形胶质细胞是中枢神经系统（CNS）中的重要支持细胞，对维持神经元健康至关重要。在诸如阿尔茨海默病（AD）等神经退行性疾病中，星形胶质细胞在清除有毒的淀粉样β（Aβ）肽方面发挥着关键作用。Aβ是一种强效的神经炎症触发因子，刺激星形胶质细胞释放过量的谷氨酸和炎症因子，加剧神经元功能障碍和死亡。最近的研究强调了Rho GTPases——特别是RhoA、Rac1和Cdc42——在调节Aβ清除和神经炎症中的作用。这些细胞骨架动力学和细胞内信号通路的关键调节因子通过不同机制独立发挥作用，但可能会共同调节炎症反应。它们对星形胶质细胞结构和功能的影响延伸至调节内皮素转换酶（ECE）活性，而ECE活性可调节诸如内皮素-1（ET-1）等血管活性肽。通过这些过程，Rho GTPases影响血管通透性和神经炎症，通过影响Aβ清除和脑血管相互作用而促成AD的发病机制。了解Rho GTPases与脑血管系统之间的相互作用为AD发病机制提供了新的见解。靶向星形胶质细胞中的Rho GTPase信号通路可能提供一种有前景的治疗方法，以减轻神经炎症、增强Aβ清除并减缓疾病进展，最终改善AD患者的认知结果。
