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      Hypertension enhances A β-induced neurovascular dysfunction, promotes β-secretase activity, and leads to amyloidogenic processing of APP

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          Abstract

          Hypertension (HTN) doubles the risk of Alzheimer’s disease (AD), but the mechanisms remain unclear. Amyloid- β (A β), a key pathogenic factor in AD, induces cerebrovascular dysfunction. We hypothesized that HTN acts in concert with A β to amplify its deleterious cerebrovascular effects and to increase A β production. Infusion of angiotensin II (ANGII; intravenously) elevated blood pressure and attenuated the cerebral blood flow (CBF) response to whisker stimulation or the endothelium-dependent vasodilator acetylcholine (ACh) ( P < 0.05). Neocortical application of A β in mice receiving ANGII worsened the responses to ACh ( P < 0.05). The cerebrovascular dysfunction observed in Tg2576 mice, in which A β is elevated both in blood and in brain due to expression of mutated amyloid precursor protein (APP), was not aggravated by neocortical application of ANGII or by a 2-week administration of ‘slow pressor’ of ANGII (600 ng/kg per minute; subcutaneously). In contrast, ANGII aggravated the dysfunction in TgSwDI mice, in which A β is increased only in brain. Slow-pressor ANGII induced microvascular amyloid deposition in Tg2576 mice and enhanced β-secretase APP cleavage. In Chinese hamster ovary (CHO) cells producing A β, ANGII increased β-secretase activity, A β1–42, and the A β42/40 ratio. We conclude that HTN enhances amyloidogenic APP processing, effects that may contribute to the pathogenic interaction between HTN and AD.

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          Author and article information

          Journal
          J Cereb Blood Flow Metab
          J. Cereb. Blood Flow Metab
          JCB
          spjcb
          Journal of Cerebral Blood Flow & Metabolism
          SAGE Publications (Sage UK: London, England )
          0271-678X
          1559-7016
          January 2016
          January 2016
          : 36
          : 1 , JCBFM Clinical issue: Impact of small vessel disease on cognition
          : 241-252
          Affiliations
          [1 ]Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, New York, New York, USA
          [2 ]Appel Alzheimer's Disease Research Institute, Weill Cornell Medical College, New York, New York, USA
          Author notes
          [*]Constantino Iadecola, Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, 407 East 61st Street; RR-303, New York, New York 10065, USA. Email: coi2001@ 123456med.cornell.edu
          Article
          PMC4758560 PMC4758560 4758560 10.1038_jcbfm.2015.79
          10.1038/jcbfm.2015.79
          4758560
          25920959
          50056bd1-1f48-49c5-afd5-fb461c8dc21d
          © The Author(s) 2015
          History
          : 1 June 2015
          : 25 March 2015
          : 30 March 2015
          Categories
          Original Articles

          endothelium-dependent vasodilatation,β-CTF,functional hyperemia,Tg2576,TgSwDI

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