| First Author | Ferreira IL | Year | 2015 |
| Journal | Neurobiol Aging | Volume | 36 |
| Issue | 2 | Pages | 680-92 |
| PubMed ID | 25442114 | Mgi Jnum | J:219520 |
| Mgi Id | MGI:5621100 | Doi | 10.1016/j.neurobiolaging.2014.09.006 |
| Citation | Ferreira IL, et al. (2015) Abeta and NMDAR activation cause mitochondrial dysfunction involving ER calcium release. Neurobiol Aging 36(2):680-92 |
| abstractText | Early cognitive deficits in Alzheimer's disease (AD) seem to be correlated to dysregulation of glutamate receptors evoked by amyloid-beta (Abeta) peptide. Abeta interference with the activity of N-methyl-d-aspartate receptors (NMDARs) may be a relevant factor for Abeta-induced mitochondrial toxicity and neuronal dysfunction. To evaluate the role of mitochondria in NMDARs activation mediated by Abeta, we followed in situ single-cell simultaneous measurement of cytosolic free Ca(2+)(Cai(2+)) and mitochondrial membrane potential in primary cortical neurons. Our results show that direct exposure to Abeta + NMDA largely increased Cai(2+) and induced immediate mitochondrial depolarization, compared with Abeta or NMDA alone. Mitochondrial depolarization induced by rotenone strongly inhibited the rise in Cai(2+) evoked by Abeta or NMDA, suggesting that mitochondria control Ca(2+) entry through NMDARs. However, incubation with rotenone did not preclude mitochondrial Ca(2+) (mitCa(2+)) retention in cells treated with Abeta. Abeta-induced Cai(2+) and mitCa(2+) rise were inhibited by ifenprodil, an antagonist of GluN2B-containing NMDARs. Exposure to Abeta + NMDA further evoked a higher mitCa(2+) retention, which was ameliorated in GluN2B(-/-) cortical neurons, largely implicating the involvement of this NMDAR subunit. Moreover, pharmacologic inhibition of endoplasmic reticulum (ER) inositol-1,4,5-triphosphate receptor (IP3R) and mitCa(2+) uniporter (MCU) evidenced that Abeta + NMDA-induced mitCa(2+) rise involves ER Ca(2+) release through IP3R and mitochondrial entry by the MCU. Altogether, data highlight mitCa(2+) dyshomeostasis and subsequent dysfunction as mechanisms relevant for early neuronal dysfunction in AD linked to Abeta-mediated GluN2B-composed NMDARs activation. |
