Calcium sensing receptor mediated the excessive generation of β-amyloid peptide induced by hypoxia in vivo and in vitro

Biochem Biophys Res Commun. 2015 Apr 17;459(4):568-73. doi: 10.1016/j.bbrc.2015.02.141. Epub 2015 Mar 4.


Hypoxia played an important role in the pathogenesis of AD. Hypoxia increased Aβ formation, then caused Alzheimer's disease. Calcium sensing receptor (CaSR) was involved in the regulation of cell growth, differentiation, hormonal secretion and other physiological function. Increasing evidence supported CaSR might play a more prominent role in susceptibility to AD, but the role of CaSR in Aβ overproduction induced by hypoxia and its mechanisms remain unclear. To investigate whether CaSR mediated the overproduction of Aβ induced by hypoxia, immunoblot and immunochemistry were employed to determine the expression of CaSR and BACE1 in hippocampal neurons and tissue and Ca(2+) image system was used to measure [Ca(2+)]i in hippocampal neurons. The content of Aβ was detected with ELISA kits. Our research found that hypoxia increased the expression of CaSR in hippocampal neurons and tissue and [Ca(2+)]i in hippocampal neurons. Calhex 231, a selective blocher of CaSR, inhibited the increase in [Ca(2+)]i induced by hypoxia. Hypoxia or GdCl3, an agonist of CaSR, increased the expression of BACE1 in hippocampal neurons and tissue, but Calhex 231 or Xesto C (a selective inhibitor of IP3 receptor) partly prevented hypoxia-induced BACE1 overexpression. Hypoxia or GdCl3 increased the content of Aβ42 and Aβ40 in hippocampal tissue, however Calhex 231 or Xesto C prevented hypoxia-induced the overproduction of Aβ42 and Aβ40 partly. Based on the above data, we suggested that hypoxia increased [Ca(2+)]i by elevated CaSR expression to promote BACE1 expression, thereby resulting in the overproduction of Aβ42 and Aβ40.

Keywords: Aβ; BACE1; Ca(2+); Calcium sensing receptor; Hypoxia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid beta-Peptides / biosynthesis*
  • Animals
  • Hypoxia / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Calcium-Sensing / physiology*


  • Amyloid beta-Peptides
  • Receptors, Calcium-Sensing