Physiology and Pharmacology of Chronic Diseases (FIFAEC), Molecular Medicine and Chronic Diseases Research Centre (CIMUS), University of Santiago de Compostela, 15782 Santiago de Compostela, Spain.
Pharmaceutical Sciences Graduate Program, Vila Velha University, Vila Velha 29102-920, ES, Brazil.
Cells. 2021 Jul 31;10(8):1951. doi: 10.3390/cells10081951.
The vascular hypothesis used to explain the pathophysiology of Alzheimer's disease (AD) suggests that a dysfunction of the cerebral microvasculature could be the beginning of alterations that ultimately leads to neuronal damage, and an abnormal increase of the blood-brain barrier (BBB) permeability plays a prominent role in this process. It is generally accepted that, in physiological conditions, cyclic AMP (cAMP) plays a key role in maintaining BBB permeability by regulating the formation of tight junctions between endothelial cells of the brain microvasculature. It is also known that intracellular cAMP signaling is highly compartmentalized into small nanodomains and localized cAMP changes are sufficient at modifying the permeability of the endothelial barrier. This spatial and temporal distribution is maintained by the enzymes involved in cAMP synthesis and degradation, by the location of its effectors, and by the existence of anchor proteins, as well as by buffers or different cytoplasm viscosities and intracellular structures limiting its diffusion. This review compiles current knowledge on the influence of cAMP compartmentalization on the endothelial barrier and, more specifically, on the BBB, laying the foundation for a new therapeutic approach in the treatment of AD.
用于解释阿尔茨海默病 (AD) 病理生理学的血管假说表明，脑微血管功能障碍可能是导致神经元损伤的最初改变，而血脑屏障 (BBB) 通透性的异常增加在这一过程中起着突出的作用。人们普遍认为，在生理条件下，环腺苷酸 (cAMP) 通过调节脑微血管内皮细胞之间的紧密连接形成，在维持 BBB 通透性方面发挥关键作用。人们还知道，细胞内 cAMP 信号转导高度区室化到小纳米域中，局部 cAMP 变化足以改变内皮屏障的通透性。这种时空分布由参与 cAMP 合成和降解的酶、其效应物的位置以及锚定蛋白的存在以及缓冲液或不同细胞质粘度和限制其扩散的细胞内结构来维持。这篇综述总结了 cAMP 区室化对内皮屏障的影响的最新知识，更具体地说，对 BBB 的影响，为 AD 的治疗提供了一种新的治疗方法的基础。
