Partial loss of endothelial nitric oxide leads to increased cerebrovascular beta amyloid

Susan A. Austin, Zvonimir S Katusic

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

Cerebral amyloid angiopathy (CAA) is present in over half of the elderly population and in 80–90% of Alzheimer’s disease (AD) patients. CAA is defined by the deposition of beta amyloid (Aβ) in small cerebral arteries and capillaries. Cardiovascular risk factors are associated with an increased incidence of CAA. We utilized 18-month-old endothelial nitric oxide synthase (eNOS) heterozygous knockout (+/−) mice, a clinically relevant model of endothelial dysfunction, to examine the role of endothelial nitric oxide (NO) in vascular Aβ accumulation. eNOS+/− mice had significantly higher vascular levels of Aβ40 (P < 0.05). Aβ42 was not detected. There was no difference in Aβ in brain tissue. Amyloid precursor protein and β-site APP cleavage enzyme 1 protein levels were unaltered, while levels of the α-secretase enzyme, a disintegrin and metalloproteinase 10, were significantly lower in eNOS + /− microvascular tissue (P < 0.05). Insulin degrading enzyme and low-density lipoprotein receptor-related protein 1 were significantly increased in eNOS+/− microvascular tissue, most likely an adaptive response to locally higher Aβ concentrations. Lastly, catalase and CuZn superoxide dismutase were significantly elevated in eNOS+/− microvascular tissue (P < 0.05). These data demonstrate decreased availability of endothelial NO leads to increased cerebrovascular concentration of Aβ along with compensatory mechanisms to protect the vasculature.

Original languageEnglish (US)
JournalJournal of Cerebral Blood Flow and Metabolism
DOIs
StateAccepted/In press - Jan 1 2019

Keywords

  • ADAM10
  • beta amyloid
  • cerebral amyloid angiopathy
  • cerebrovascular
  • endothelial nitric oxide synthase

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine

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