Amyloid-β disrupts unitary calcium entry through endothelial NMDA receptors in mouse cerebral arteries

Emily C. Peters, Michael T. Gee, Lukas N. Pawlowski, Allison M. Kath, Felipe D. Polk, Christopher J. Vance, Juliana L. Sacoman, Paulo W. Pires

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Transient increases in intracellular Ca2+ activate endothelium-dependent vasodilatory pathways. This process is impaired in cerebral amyloid angiopathy, where amyloid-β(1-40) accumulates around blood vessels. In neurons, amyloid-β impairs the Ca2+-permeable N-methyl-D-aspartate receptor (NMDAR), a mediator of endothelium-dependent dilation in arteries. We hypothesized that amyloid-β(1-40) reduces NMDAR-elicited Ca2+ signals in mouse cerebral artery endothelial cells, blunting dilation. Cerebral arteries isolated from 4-5 months-old, male and female cdh5:Gcamp8 mice were used for imaging of unitary Ca2+ influx through NMDAR (NMDAR sparklets) and intracellular Ca2+ transients. The NMDAR agonist NMDA (10 µmol/L) increased frequency of NMDAR sparklets and intracellular Ca2+ transients in endothelial cells; these effects were prevented by NMDAR antagonists D-AP5 and MK-801. Next, we tested if amyloid-β(1-40) impairs NMDAR-elicited Ca2+ transients. Cerebral arteries incubated with amyloid-β(1-40) (5 µmol/L) exhibited reduced NMDAR sparklets and intracellular Ca2+ transients. Lastly, we observed that NMDA-induced dilation of pial arteries is reduced by acute intraluminal amyloid-β(1-40), as well as in a mouse model of Alzheimer’s disease, the 5x-FAD, linked to downregulation of Grin1 mRNA compared to wild-type littermates. These data suggest that endothelial NMDAR mediate dilation via Ca2+-dependent pathways, a process disrupted by amyloid-β(1-40) and impaired in 5x-FAD mice.

Original languageEnglish (US)
Pages (from-to)145-161
Number of pages17
JournalJournal of Cerebral Blood Flow and Metabolism
Volume42
Issue number1
DOIs
StatePublished - Jan 2022

Keywords

  • N-methyl-D-aspartate receptor
  • amyloid-β
  • cerebral amyloid angiopathy
  • endothelium Ca signaling
  • endothelium-dependent dilation

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine

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