title: Hypertension induces brain β-amyloid accumulation, cognitive impairment, and memory deterioration through activation of receptor for advanced glycation end products in brain vasculature.
abstract: Although epidemiological data associate hypertension with a strong predisposition to develop Alzheimer disease, no mechanistic explanation exists so far. We developed a model of hypertension, obtained by transverse aortic constriction, leading to alterations typical of Alzheimer 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 disease of hypertensive mice. We focused on receptor for advanced glycation end products (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 upregulation in brain vessels of the 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 transverse aortic coarctation mice was induced by increased circulating advanced glycation end products and sustained by their later deposition in brain vessels. Interestingly, a daily treatment with an advanced glycation end product inhibitor or antioxidant prevented the development of Alzheimer 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 disease, suggesting that inhibiting this target can limit the onset of vascular-related Alzheimer disease.
authors.affiliation: Department of Molecular Medicine, Sapienza University of Rome, c/o IRCCS Neuromed, Località Camerelle, 86077 Pozzilli, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Carnevale
authors.forename: Giada
authors.initials: G
authors.lastname: Mascio
authors.forename: Ivana
authors.initials: I
authors.lastname: D'Andrea
authors.forename: Valentina
authors.initials: V
authors.lastname: Fardella
authors.forename: Robert D
authors.initials: RD
authors.lastname: Bell
authors.forename: Igor
authors.initials: I
authors.lastname: Branchi
authors.forename: Fabio
authors.initials: F
authors.lastname: Pallante
authors.forename: Berislav
authors.initials: B
authors.lastname: Zlokovic
authors.forename: Shirley Shidu
authors.initials: SS
authors.lastname: Yan
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Lembo
mesh_terms: D014013:1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt / Q000494:pharmacology; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001017:Aortic Coarctation / Q000150:complications; D001808:Blood Vessels / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D015153:Blotting, Western; D001921:Brain / Q000098:blood supply / Q000378:metabolism* / Q000503:physiopathology; D003072:Cognition Disorders / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D017127:Glycation End Products, Advanced / Q000378:metabolism; D006146:Guanidines / Q000494:pharmacology; D006973:Hypertension / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D018782:Maze Learning / Q000187:drug effects; D008569:Memory Disorders / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D016229:Amyloid beta-Peptides; D004791:Enzyme Inhibitors; D017127:Glycation End Products, Advanced; D006146:Guanidines; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D014013:1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt; C004479:pimagedine