Aβ and NMDAR activation cause mitochondrial dysfunction involving ER calcium release
Ildete Luísa Ferreira1, Elisabete Ferreiro1, Jeannette Schmidt2
1Center for Neuroscience and Cell Biology (CNC), University of Coimbra, Coimbra, Portugal; Institute for Interdisciplinary Research of the University of Coimbra (IIIUC), Coimbra, Portugal.
Neurobiology of Aging
|December 3, 2014
Summary
Amyloid-beta peptides in Alzheimer's disease disrupt calcium signaling via N-methyl-d-aspartate receptors (NMDARs), leading to mitochondrial dysfunction and early cognitive deficits. Targeting GluN2B-containing NMDARs may offer therapeutic potential.
Area of Science:
- Neuroscience
- Molecular Biology
- Cell Biology
Background:
- Early cognitive deficits in Alzheimer's disease (AD) are linked to amyloid-beta (Aβ) peptide-induced glutamate receptor dysregulation.
- Aβ interference with N-methyl-d-aspartate receptors (NMDARs) may contribute to mitochondrial toxicity and neuronal dysfunction in AD.
Purpose of the Study:
- To investigate the role of mitochondria in NMDARs activation mediated by Aβ.
- To elucidate the mechanisms of Aβ-induced calcium (Ca2+) dysregulation and mitochondrial dysfunction in neurons.
Main Methods:
- In situ single-cell simultaneous measurement of cytosolic free Ca2+ (Cai2+) and mitochondrial membrane potential in primary cortical neurons.
- Exposure to Aβ, NMDA, or combined Aβ + NMDA.
- Pharmacological inhibition of mitochondrial function (rotenone), NMDARs (ifenprodil), endoplasmic reticulum (ER) inositol-1,4,5-triphosphate receptor (IP3R), and mitochondrial Ca2+ uniporter (MCU).
Main Results:
- Aβ + NMDA significantly increased Cai2+ and induced immediate mitochondrial depolarization compared to Aβ or NMDA alone.
- Mitochondrial depolarization inhibited Aβ- or NMDA-evoked Cai2+ rise, indicating mitochondria control NMDARs Ca2+ entry.
- Aβ-induced mitochondrial Ca2+ (mitCa2+) retention was not prevented by rotenone but was inhibited by ifenprodil, implicating GluN2B-containing NMDARs.
- Aβ + NMDA-induced mitCa2+ rise involved ER Ca2+ release via IP3R and mitochondrial uptake via MCU.
Conclusions:
- Mitochondrial Ca2+ dyshomeostasis and subsequent dysfunction are key mechanisms in early AD neuronal dysfunction.
- Aβ-mediated activation of GluN2B-containing NMDARs contributes to these detrimental effects.
- Targeting GluN2B-containing NMDARs, IP3R, and MCU may represent therapeutic strategies for AD.
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