218 A lzheimer disease (AD) accounts for 60% to 80% of dementia cases and represents the most common cause of dementia among the elderly. 1 AD is a chronic neurodegenerative disorder characterized by the development of cortical extracel- lular amyloid plaques, mainly consisting of amyloid β peptide (Aβ) and the intracellular neurofibrillary tangles formed by the aggregated tau protein. 2 Aβ is a proteolytic cleavage product of amyloid precursor protein (APP), ubiquitously expressed in the body. APP is processed sequentially by γ- and β-secretases to generate a heterogeneous group of peptides among which Aβ42 and Aβ40 are believed to be particularly important in the pathogenesis of AD. 3 Although Aβ remains in the focus of AD research, the pathogenesis of AD is largely undefined and effec- tive treatments are still not available. 4 The interest in the role of vascular factors in pathogenesis of neurodegenerative dementias has grown steadily during the past decade. It is now well recognized that cerebrovascular dysfunction could be an essential factor in the pathogenesis of many types of dementia and significantly affects both inci- dence and course of the disease. 5 Cerebrovascular impairment, including cerebral amyloid angi- opathy, brain–blood barrier impairment, and small vessel disease, is frequently observed in patients with AD and could influence clinical manifestation and severity of AD and contribute to cog- nitive decline. 6 In addition, cardiovascular risk factors have been associated with higher risk of developing AD. 7,8 Cardiovascular disease preventing strategies, like antihypertensive medications, were correlated with better mental health outcomes later in Abstract—Cerebrovascular impairment is frequent in patients with Alzheimer disease and is believed to influence clinical manifestation and severity of the disease. Cardiovascular risk factors, especially hypertension, have been associated with higher risk of developing Alzheimer disease. To investigate the mechanisms underlying the hypertension, Alzheimer disease cross talk, we established a mouse model of dual pathology by infusing hypertensive doses of angiotensin II into transgenic APPPS1 mice overexpressing mutated human amyloid precursor and presenilin 1 proteins. At 4.5 months, at the early stage of disease progression, only hypertensive APPPS1 mice presented impairment of temporal order memory performance in the episodic-like memory task. This cognitive deficit was associated with an increased number of cortical amyloid deposits (223±5 versus 207±5 plaques/mm 2 ; P<0.05) and a 2-fold increase in soluble amyloid levels in the brain and in plasma. Hypertensive APPPS1 mice presented several cerebrovascular alterations, including a 25% reduction in cerebral microvessel density and a 30% to 40% increase in cerebral vascular amyloid deposits, as well as a decrease in vascular endothelial growth factor A expression in the brain, compared with normotensive APPPS1 mice. Moreover, the brain levels of nitric oxide synthase 1 and 3 and the nitrite/nitrate levels were reduced in hypertensive APPPS1 mice (by 49%, 34%, and 33%, respectively, compared with wild-type mice; P<0.05). Our results indicate that hypertension accelerates the development of Alzheimer disease–related structural and functional alterations, partially through cerebral vasculature impairment and reduced nitric oxide production. (Hypertension. 2015;65:218-224. DOI: 10.1161/HYPERTENSIONAHA.114.04139.) • Online Data Supplement Key Words: Alzheimer Disease ■ hypertension ■ models, animal ■ nitric oxide Received June 25, 2014; first decision July 4, 2014; revision accepted September 2, 2014. From the Institut des Vaisseaux et du Sang, Paris, France (D.C., M.P., D.B.-Y., T.M.-R., B.I.L.); INSERM, U965, Paris, France (D.C., M.P., D.B.-Y., P.B., M.P., N.K., T.M.-R.); Max Planck Institute of Experimental Medicine, Göttingen, Germany (E.D.); Université Paris Diderot, Sorbonne Paris Cité, Paris, France (P.B., M.P., N.K., B.I.L.); AP-HP, Hôpital Lariboisière, Paris, France (P.B., N.K.); AP-HP, Hôpital Bichat—Claude-Bernard, Paris, France (J.B.); CNRS UMR 8256, Paris, France (J.M.); and INSERM, U970, Paris, France (B.I.L.). *These authors contributed equally to this work. This work has been presented in the Ninth International Workshop on structure and function of the vascular system held in Paris (France), February 6 to 8, 2014. The online-only Data Supplement is available with this article at http://hyper.ahajournals.org/lookup/suppl/doi:10.1161/HYPERTENSIONAHA. 114.04139/-/DC1. Correspondence to Bernard Levy, Institut des Vaisseaux et du Sang, Hôpital Lariboisière, 8 rue Guy Patin, 75475 Paris Cedex 10, France. E-mail bernard.levy@inserm.fr Hypertension Accelerates the Progression of Alzheimer-Like Pathology in a Mouse Model of the Disease Diana Cifuentes,* Marine Poittevin,* Ekrem Dere, Dong Broquères-You, Philippe Bonnin, Joëlle Benessiano, Marc Pocard, Jean Mariani, Nathalie Kubis, Tatyana Merkulova-Rainon,* Bernard I. Lévy* © 2014 American Heart Association, Inc. Hypertension is available at http://hyper.ahajournals.org DOI: 10.1161/HYPERTENSIONAHA.114.04139 See Editorial Commentary, pp 36–38 Mouse Model of Alzheimer Disease and Hypertension by guest on June 7, 2016 http://hyper.ahajournals.org/ Downloaded from by guest on June 7, 2016 http://hyper.ahajournals.org/ Downloaded from by guest on June 7, 2016 http://hyper.ahajournals.org/ Downloaded from by guest on June 7, 2016 http://hyper.ahajournals.org/ Downloaded from by guest on June 7, 2016 http://hyper.ahajournals.org/ Downloaded from by guest on June 7, 2016 http://hyper.ahajournals.org/ Downloaded from by guest on June 7, 2016 http://hyper.ahajournals.org/ Downloaded from by guest on June 7, 2016 http://hyper.ahajournals.org/ Downloaded from by guest on June 7, 2016 http://hyper.ahajournals.org/ Downloaded from by guest on June 7, 2016 http://hyper.ahajournals.org/ Downloaded from