Endothelin-converting enzyme-1 activity, endothelin-1 production, and free radical-dependent vasoconstriction in Alzheimer's disease

Jennifer C. Palmer*, Hannah M. Tayler, Seth Love

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

41 Citations (Scopus)

Abstract

Alzheimer's disease (AD) patients have reduced cerebral blood flow. This precedes dementia and may contribute to its progression. In mice that overexpress amyloid-β protein precursor, cerebral blood flow declines before the development of plaques or cognitive abnormalities. In the brain, endothelin-1 (ET-1) is a locally acting vasoconstrictor, produced in neurons by endothelin-converting enzyme (ECE)-2 and in endothelial cells by ECE-1. Both ECEs are also capable of cleaving amyloid-β (Aβ). We previously showed ECE-2 and ET-1 to be elevated in postmortem temporal cortex from AD patients, and ECE-2 expression and ET-1 release to be upregulated by Aβ42 in vitro. We have now studied isolated leptomeningeal blood vessels from postmortem brains and found that although ECE-1 level is reduced, ECE-1 activity and ET-1 level are significantly elevated in AD vessels. This is specific to AD as there is no specific change in vascular dementia vessels. In primary cultures of human brain endothelial cells, both Aβ40 and Aβ42 caused a significant increase in ET-1 release, the increase being particularly pronounced with Aβ40. In view of previous studies implicating free radicals in the endothelial dysfunction caused by Aβ40, we examined whether Aβ-mediated ET-1 release could be prevented by the antioxidant superoxide dismutase. Addition of superoxide dismutase to cells exposed to Aβ40 prevented the increase in the concentration of ET-1. Our findings indicate that cerebral vasoconstriction induced by Aβ results in part from a free radical-mediated increase in ECE-1 activity and ET-1 production. © 2013 - IOS Press and the authors. All rights reserved.

Original languageEnglish
Pages (from-to)577-587
Number of pages11
JournalJournal of Alzheimer's Disease
Volume36
Issue number3
DOIs
Publication statusPublished - 19 Aug 2013

Keywords

  • Alzheimer's disease
  • cerebral blood flow
  • endothelin-1
  • free radicals
  • vascular dysfunction

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