The bradykinin B1 receptor regulates Aβ deposition and neuroinflammation in Tg-SwDI mice

Am J Pathol. 2013 May;182(5):1740-9. doi: 10.1016/j.ajpath.2013.01.021. Epub 2013 Mar 5.

Abstract

The deposition of amyloid-β peptides (Aβ) in the cerebral vasculature, a condition known as cerebral amyloid angiopathy, is increasingly recognized as an important component leading to intracerebral hemorrhage, neuroinflammation, and cognitive impairment in Alzheimer disease (AD) and related disorders. Recent studies demonstrated a role for the bradykinin B1 receptor (B1R) in cognitive deficits induced by Aβ in mice; however, its involvement in AD and cerebral amyloid angiopathy is poorly understood. Herein, we investigated the effect of B1R inhibition on AD-like neuroinflammation and amyloidosis using the transgenic mouse model (Tg-SwDI). B1R expression was found to be up-regulated in brains of Tg-SwDI mice, specifically in the vasculature, neurons, and astrocytes. Notably, administration of the B1R antagonist, R715, to 8-month-old Tg-SwDI mice for 8 weeks resulted in higher Aβ40 levels and increased thioflavin S-positive fibrillar Aβ deposition. Moreover, blockage of B1R inhibited neuroinflammation, as evidenced by the decreased accumulation of activated microglia and reactive astrocytes, diminished NF-κB activation, and reduced cytokine and chemokine levels. Together, our results indicate that B1R activation plays an important role in limiting the accumulation of Aβ in AD-like brain, likely through the regulation of activated glial cell accumulation and release of pro-inflammatory mediators. Therefore, the modulation of the receptor may represent a novel therapeutic approach for AD.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid beta-Peptides / metabolism*
  • Animals
  • Bradykinin B1 Receptor Antagonists
  • Brain / metabolism
  • Brain / pathology
  • Brain / physiopathology
  • Cognition
  • Humans
  • Inflammation / metabolism*
  • Inflammation / pathology*
  • Inflammation / physiopathology
  • Mice
  • Mice, Transgenic
  • Nervous System / metabolism*
  • Nervous System / pathology*
  • Nervous System / physiopathology
  • Neuroglia / metabolism
  • Neuroglia / pathology
  • Protein Processing, Post-Translational
  • Receptor, Bradykinin B1 / metabolism*
  • Up-Regulation

Substances

  • Amyloid beta-Peptides
  • Bradykinin B1 Receptor Antagonists
  • Receptor, Bradykinin B1