Endothelial dysfunction, Alzheimer disease and RAGE: mechanism(s) and potential therapeutic interventions

Endothelial dysfunction in Alzheimer Disease (AD) may contribute to cerebral blood flow dysregulation and exacerbate the cognitive decline. Numerous studies have reported effects of beta amyloid peptides (Aβ) on vascular physiology, while retrospective autoptical studies in humans have shown correlation between AD-like lesions and vascular risk factors, in particular type 2 diabetes mellitus. In many instances, however, age-related cognitive disorders occurs either with a predominant vascular involvement (ischemic infarcts, lacunes, cerebral hemorrhages, white matter lesions, blood-brain barrier dysfunction, cerebral amyloid angiopathy, and microvascular degeneration) or with typical neuro-parenchymal lesions (tangle, plaques,…) in the absence of major vascular lesions. These observations challenge the idea that endothelial dysfunction is mechanistically linked to dysregulation in Aβ production and/or processing, rather suggesting that angiopathy and neurodegeneration may occur independently. In vitro studies and AD animal models have not provided so far molecular target(s) accountable for the action of Aβ on vascular physiology. One of this targets could be the Receptor for Advanced Glycated End products (RAGE), a transmembrane protein that recognizes both Aβ and AGEs, whose activation is responsible for inflammatory signaling in both vascular and neurological disease. Because evidence for activation of RAGE by Aβ is robust, here we discuss its potential impact on endothelial function and vascular physiology.