Amyloid-β disrupts unitary calcium entry through endothelial NMDA receptors in mouse cerebral arteries
| Autor: | Paulo W. Pires, Allison M Kath, Michael T. Gee, Juliana L Sacoman, Emily C Peters, Felipe D Polk, Christopher J. Vance, Lukas N Pawlowski |
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| Rok vydání: | 2021 |
| Předmět: |
Male
Amyloid β Cerebral arteries Mice Transgenic Vasodilation Receptors N-Methyl-D-Aspartate Mice Alzheimer Disease mental disorders medicine Animals Calcium Signaling Calcium entry Amyloid beta-Peptides Chemistry Original Articles Cerebral Arteries medicine.disease Peptide Fragments Cell biology Disease Models Animal Endothelium dependent dilation nervous system Neurology NMDA receptor Calcium Female Endothelium Vascular Neurology (clinical) Cerebral amyloid angiopathy Cardiology and Cardiovascular Medicine Intracellular |
| Zdroj: | J Cereb Blood Flow Metab |
| ISSN: | 1559-7016 0271-678X |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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