Abstract
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.
Highlights
Median age increases, especially in developed countries, are accompanied by an increase in the prevalence of several types of primary degenerative dementias, most of them associated with the elderly
Other highly useful sensors were developed for the performance of cyclic AMP (cAMP) signal sublocation experiments, such as the one that uses mutants of the green fluorescent protein (GFP) fused to the different subunits of protein kinase A (PKA) [76] or those based on the cAMP-binding domains of the exchange proteins directly activated by cAMP (Epac) [77]
In the search for new, successful, therapeutic options to treat Alzheimer’s disease (AD), the vascular hypothesis paves the way for potential strategies related to the improvement of blood flow at the cerebral microvascular and protection of the blood–brain barrier (BBB), as highlighted in this review
Summary
Especially in developed countries, are accompanied by an increase in the prevalence of several types of primary degenerative dementias, most of them associated with the elderly. It follows—from the above—that a highly selective BBB permeability is essential for the maintenance of healthy brain functioning In this sense, it is known that the cAMP signaling pathway plays a very prominent role in the regulation of cerebrovascular endothelial permeability, as reviewed . Later studies served to demonstrate that cAMP signaling participates in a prominent way in the regulation of endothelial permeability, and a rise in its concentration enhances barrier functions [10,25,62,63,64,65]. It is no surprise that study results have reported that, contrary to the widely accepted notion, an endothelial increase of cAMP could enhance vascular permeability, an effect that would be mediated by transcriptional small guanosine triphosphate hydrolase Ras-related protein (RRAS) suppression [70]. CAMP-activated signal transduction mechanisms can lead to different responses, depending on the cell area in which they take place [71,72,73,74]
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