Cellular and Molecular Neurobiology Area, Group of Neuroscience of Antioquia, SIU, University of Antioquia, Medellín, Colombia.
Institute of Biology, Faculty of Exact and Natural Sciences, University of Antioquia, Medellín, Colombia.
J Alzheimers Dis. 2021;82(s1):S141-S161. doi: 10.3233/JAD-200730.
The neurovascular unit (NVU) is responsible for synchronizing the energetic demand, vasodynamic changes, and neurochemical and electrical function of the brain through a closed and interdependent interaction of cell components conforming to brain tissue. In this review, we will focus on cyclin-dependent kinase 5 (CDK5) as a molecular pivot, which plays a crucial role in the healthy function of neurons, astrocytes, and the endothelium and is implicated in the cross-talk of cellular adhesion signaling, ion transmission, and cytoskeletal remodeling, thus allowing the individual and interconnected homeostasis of cerebral parenchyma. Then, we discuss how CDK5 overactivation affects the integrity of the NVU in Alzheimer's disease (AD) and cognitive impairment; we emphasize how CDK5 is involved in the excitotoxicity spreading of glutamate and Ca2+ imbalance under acute and chronic injury. Additionally, we present pharmacological and gene therapy strategies for producing partial depletion of CDK5 activity on neurons, astrocytes, or endothelium to recover neuroplasticity and neurotransmission, suggesting that the NVU should be the targeted tissue unit in protective strategies. Finally, we conclude that CDK5 could be effective due to its intervention on astrocytes by its end feet on the endothelium and neurons, acting as an intermediary cell between systemic and central communication in the brain. This review provides integrated guidance regarding the pathogenesis of and potential repair strategies for AD.
神经血管单元 (NVU) 通过构成脑组织的细胞成分的封闭和相互依存的相互作用，负责同步大脑的能量需求、血管动力学变化以及神经化学和电功能。在这篇综述中，我们将重点关注周期蛋白依赖性激酶 5 (CDK5) 作为分子枢轴，它在神经元、星形胶质细胞和内皮细胞的健康功能中发挥着至关重要的作用，并涉及细胞黏附信号转导、离子传递和细胞骨架重塑的交叉对话，从而允许大脑实质的个体和相互连接的内稳态。然后，我们讨论了 CDK5 的过度激活如何影响阿尔茨海默病 (AD) 和认知障碍中 NVU 的完整性；我们强调了 CDK5 如何参与谷氨酸的兴奋毒性扩散和急性和慢性损伤下的 Ca2+ 失衡。此外，我们提出了药理学和基因治疗策略，以产生神经元、星形胶质细胞或内皮细胞上 CDK5 活性的部分耗竭，以恢复神经可塑性和神经传递，这表明 NVU 应该是保护性策略的靶向组织单位。最后，我们得出结论，由于 CDK5 通过其在血管内皮细胞和神经元上的终足对星形胶质细胞的干预作用，作为大脑中全身和中枢通讯之间的中介细胞，它可能是有效的。这篇综述为 AD 的发病机制和潜在修复策略提供了综合指导。
