cAMP Compartmentalization in Cerebrovascular Endothelial Cells: New Therapeutic Opportunities in Alzheimer's Disease

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.

Keywords: AKAP; Alzheimer’s disease; Epac proteins; adenylyl cyclases; blood brain barrier; cyclic AMP; endothelium; intracellular compartmentalization; phosphodiesterase; protein kinase A.

Figure 1

cAMP in the vascular theory of Alzheimer disease. cAMP exerts a protective effect on the integrity of the endothelium in the blood–brain barrier against processes that cause its pathological fenestration and the development of neurodegenerative diseases. ACs: adenylyl cyclases; BBB: blood brain barrier; CNS: central nervous system; PDE: phosphodiesterase; ROS: reactive oxygen species. For more details, see text.

Figure 2

Suggested model of compartmentalization of the cAMP signal in endothelial cells of the cerebral microvasculature and its participation in the integrity of the barrier function. AC: adenylyl cyclase; AKAP: A-kinase anchor proteins; GPCR: G-protein coupled receptor; PDE: phosphodiesterase; PKA: protein kinase A; sAC: soluble adenylyl cyclase; TJ: Tight junction. For more details, see text.