β-amyloid accumulation in neurovascular units following brain embolism

Feng Han, Kohji Fukunaga

Research output: Contribution to journalReview article

5 Citations (Scopus)

Abstract

Nitric oxide (NO) toxicity is in part mediated by generation of peroxynitrite with concomitant production of superoxide under pathological brain conditions such as ischemia and Alzheimer's disease. The pathophysiological relevance of endothelial nitric oxide synthase (eNOS) to brain embolism-induced neurovascular injury has not been documented. We found that microsphere embolism (ME)-induced aberrant eNOS expression in vascular endothelial cells likely mediates blood-brain barrier (BBB) disruption via peroxynitrite formation and in turn causes brain edema. We also demonstrated that a mild ME model was useful for investigating the sequential events of neurovascular injury followed by β-amyloid accumulation and tau hyperphosphorylation. Indeed, immunoblotting of purified brain microvessels revealed that β-amyloid accumulation significantly increased one week after ME induction and remained elevated for twelve weeks in those animals. Moreover, we also confirmed that peroxynitrite formation and eNOS uncoupling-mediated superoxide generation in microvessels are inhibited by a novel calmodulin inhibitor. Thus, peroxynitrite formation via elevated eNOS is associated with endothelial cell injury with concomitant β-amyloid accumulation in microvessels of aged rats. In this review, we focus on the detrimental effects of eNOS expression following brain embolism and introduce an attractive model representing progressive Alzheimer's disease pathology in brain.

Original languageEnglish
Pages (from-to)101-109
Number of pages9
JournalJournal of Pharmacological Sciences
Volume111
Issue number2
DOIs
Publication statusPublished - 2009 Nov 4

Keywords

  • Calmodulin
  • Endothelial nitric oxide synthase (eNOS)
  • Microsphere embolism
  • Nitric oxide (NO)
  • Peroxynitrite
  • β-amyloid

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Fingerprint Dive into the research topics of 'β-amyloid accumulation in neurovascular units following brain embolism'. Together they form a unique fingerprint.

  • Cite this