Endothelin-1 is Elevated in Alzheimer's Disease and Upregulated by Amyloid-beta

Jennifer C. Palmer*, Rachel Barker, Patrick G. Kehoe, Seth Love

*Corresponding author for this work

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

66 Citations (Scopus)

Abstract

Vascular dysfunction and lowered cerebral blood flow are thought to contribute to the development and progression of Alzheimer's disease (AD). Endothelin-1 (ET-1) is a potent vasoconstrictor, the production of which is mainly catalyzed by endothelin-converting enzymes (ECEs). We previously showed that ECE-2 is upregulated by amyloid-beta (A beta), and its expression elevated in AD postmortem brain tissue. We have now investigated whether there is a concomitant increase in ET-1. We studied temporal cortex from 20 cases of sporadic AD and 20 matched controls. The cellular distribution of ET-1 was assessed immunohistochemically in paraffin sections. PreproET-1 (EDN1) mRNA and ET-1 protein were measured in homogenates of superior temporal cortex by real-time PCR and sandwich ELISA respectively. Cultured SH-SY5Y human neuroblastoma cells were incubated with 10 mu M oligomeric A beta(42) for 24 h, and ET-1 protein level was measured in cell culture supernatants by sandwich ELISA. Antibody to ET-1 labeled neurons throughout the temporal cortex, and the walls of some cerebral blood vessels. ET-1 mRNA measured in the temporal neocortex was significantly elevated in AD when normalized for expression of GAPDH (p = 0.0256) or the neuronal marker neuron-specific enolase (NSE, p = 0.0001). ET-1 protein was also significantly higher in AD than in control tissue, when adjusted for neuronal content by measurement of NSE (p = 0.0275). ET-1 protein in SH-SY5Y cell supernatant rose 1.7-fold after exposure to 10 mu M oligomeric A beta (p = 0.024). These findings provide evidence of overactivity of the endothelin system in AD, further supporting the suggestion that endothelin receptor antagonists may be of value for the treatment of this disease.

Original languageEnglish
Pages (from-to)853-861
Number of pages9
JournalJournal of Alzheimer's Disease
Volume29
Issue number4
DOIs
Publication statusPublished - Feb 2012

Keywords

  • vasoconstriction
  • HUMAN BRAIN
  • CONVERTING ENZYME-2
  • HYPOPERFUSION
  • DEMENTIA
  • CEREBRAL-BLOOD-FLOW
  • GENE-EXPRESSION
  • SYSTEM
  • Alzheimer's disease
  • A-BETA
  • endothelin-1
  • PEPTIDE
  • cerebral ischemia
  • cerebrovascular disorders
  • TRANSGENIC MICE
  • amyloid-beta
  • cerebrovascular circulation

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