title: Hypertension accelerates the progression of Alzheimer-like pathology in a mouse model of the disease.
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.
authors.affiliation: 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.).
authors.forename: Diana
authors.initials: D
authors.lastname: Cifuentes
authors.affiliation: 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.).
authors.forename: Marine
authors.initials: M
authors.lastname: Poittevin
authors.affiliation: 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.).
authors.forename: Ekrem
authors.initials: E
authors.lastname: Dere
authors.affiliation: 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.).
authors.forename: Dong
authors.initials: D
authors.lastname: Broquères-You
authors.affiliation: 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.).
authors.forename: Philippe
authors.initials: P
authors.lastname: Bonnin
authors.affiliation: 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.).
authors.forename: Joëlle
authors.initials: J
authors.lastname: Benessiano
authors.affiliation: 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.).
authors.forename: Marc
authors.initials: M
authors.lastname: Pocard
authors.affiliation: 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.).
authors.forename: Jean
authors.initials: J
authors.lastname: Mariani
authors.affiliation: 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.).
authors.forename: Nathalie
authors.initials: N
authors.lastname: Kubis
authors.affiliation: 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.).
authors.forename: Tatyana
authors.initials: T
authors.lastname: Merkulova-Rainon
authors.affiliation: 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.). bernard.levy@inserm.fr.
authors.forename: Bernard I
authors.initials: BI
authors.lastname: Lévy
mesh_terms: D000544:Alzheimer Disease / Q000150:complications* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D004195:Disease Models, Animal; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005786:Gene Expression Regulation; D006973:Hypertension / Q000150:complications* / Q000235:genetics / Q000378:metabolism; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016133:Polymerase Chain Reaction; D012313:RNA / Q000235:genetics*; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D042461:Vascular Endothelial Growth Factor A; D012313:RNA
keywords: Alzheimer Disease; hypertension; models, animal; nitric oxide