کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
6804742 | 1433559 | 2015 | 39 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Aβ and NMDAR activation cause mitochondrial dysfunction involving ER calcium release
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کلمات کلیدی
موضوعات مرتبط
علوم زیستی و بیوفناوری
بیوشیمی، ژنتیک و زیست شناسی مولکولی
سالمندی
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چکیده انگلیسی
Early cognitive deficits in Alzheimer's disease (AD) seem to be correlated to dysregulation of glutamate receptors evoked by amyloid-beta (Aβ) peptide. Aβ interference with the activity of N-methyl-d-aspartate receptors (NMDARs) may be a relevant factor for Aβ-induced mitochondrial toxicity and neuronal dysfunction. To evaluate the role of mitochondria in NMDARs activation mediated by Aβ, we followed in situ single-cell simultaneous measurement of cytosolic free Ca2+(Cai2+) and mitochondrial membrane potential in primary cortical neurons. Our results show that direct exposure to Aβ + NMDA largely increased Cai2+ and induced immediate mitochondrial depolarization, compared with Aβ or NMDA alone. Mitochondrial depolarization induced by rotenone strongly inhibited the rise in Cai2+ evoked by Aβ or NMDA, suggesting that mitochondria control Ca2+ entry through NMDARs. However, incubation with rotenone did not preclude mitochondrial Ca2+ (mitCa2+) retention in cells treated with Aβ. Aβ-induced Cai2+ and mitCa2+ rise were inhibited by ifenprodil, an antagonist of GluN2B-containing NMDARs. Exposure to Aβ + NMDA further evoked a higher mitCa2+ retention, which was ameliorated in GluN2Bâ/â 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 mitCa2+ uniporter (MCU) evidenced that Aβ + NMDA-induced mitCa2+ rise involves ER Ca2+ release through IP3R and mitochondrial entry by the MCU. Altogether, data highlight mitCa2+ dyshomeostasis and subsequent dysfunction as mechanisms relevant for early neuronal dysfunction in AD linked to Aβ-mediated GluN2B-composed NMDARs activation.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Neurobiology of Aging - Volume 36, Issue 2, February 2015, Pages 680-692
Journal: Neurobiology of Aging - Volume 36, Issue 2, February 2015, Pages 680-692
نویسندگان
Ildete LuÃsa Ferreira, Elisabete Ferreiro, Jeannette Schmidt, João M. Cardoso, Cláudia M.F. Pereira, Ana LuÃsa Carvalho, Catarina R. Oliveira, A. Cristina Rego,