Although epidemiological data associate hypertension with a strong predisposition to develop Alzheimer’s Disease, no mechanistic explanation exists so far. We developed a model of hypertension, obtained by Transverse Aortic Constriction, leading to alterations typical of Alzheimer’s Disease, such as amyloid plaques, neuroinflammation, Blood Brain Barrier dysfunction and cognitive impairment, shown here for the first time. The aim of this work was to investigate the mechanisms involved in Alzheimer’s Disease of hypertensive mice. We focused on RAGE, that critically regulates Aβ transport at the Blood Brain Barrier and could be influenced by vascular factors. The hypertensive challenge had an early and sustained effect on RAGE up-regulation in brain vessels of cortex and hippocampus. Interestingly, RAGE inhibition protected from hypertension-induced Alzheimer pathology, as showed by rescue from cognitive impairment and parenchymal Aβ deposition. The increased RAGE expression in TAC mice was induced by increased circulating AGEs and sustained by their later deposition in brain vessels. Interestingly, a daily treatment with an AGEs inhibitor or antioxidant prevented the development of Alzheimer’s traits. So far, Alzheimer pathology in experimental animal models has been recognized using only transgenic mice overexpressing amyloid precursor. This is the first study demonstrating that a chronic vascular insult can activate brain vascular RAGE, favoring parenchymal Aβ deposition and the onset of cognitive deterioration. Overall we demonstrate that RAGE activation in brain vessels is a crucial pathogenetic event in hypertension-induced Alzheimer’s Disease, suggesting that inhibiting this target can limit the onset of vascular-related Alzheimer.

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The crucial role of the immune system in hypertension is now widely recognized. We previously reported that hypertensive challenges couple the nervous drive with immune system activation, but the physiological and molecular mechanisms of this connection are unknown. Here, we show that hypertensive challenges activate splenic sympathetic nerve discharge to prime immune response. More specifically, a vagus-splenic nerve drive, mediated by nicotinic cholinergic receptors, links the brain and spleen. The sympathetic discharge induced by hypertensive stimuli was absent in both coeliac vagotomized mice and in mice lacking α7nAChR, a receptor typically expressed by peripheral ganglionic neurons. This cholinergic-sympathetic pathway is necessary for T cell activation and egression on hypertensive challenges. In addition, we show that selectively thermoablating the splenic nerve prevents T cell egression and protects against hypertension. This novel experimental procedure for selective splenic denervation suggests new clinical strategies for resistant hypertension.