Aβ and NMDAR activation cause mitochondrial dysfunction involving ER calcium release

Abstract

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 Ca(2+)(Cai(2+)) and mitochondrial membrane potential in primary cortical neurons. Our results show that direct exposure to Aβ + NMDA largely increased Cai(2+) and induced immediate mitochondrial depolarization, compared with Aβ or NMDA alone. Mitochondrial depolarization induced by rotenone strongly inhibited the rise in Cai(2+) evoked by Aβ 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 Aβ. Aβ-induced Cai(2+) and mitCa(2+) rise were inhibited by ifenprodil, an antagonist of GluN2B-containing NMDARs. Exposure to Aβ + 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 Aβ + 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 Aβ-mediated GluN2B-composed NMDARs activation.

In vitro aging promotes endoplasmic reticulum (ER)-mitochondria Ca 2+ cross talk and loss of store-operated Ca 2+ entry (SOCE) in rat hippocampal neurons

“…Specifically, Aβ mobilizes ER Ca 2+ via IP 3 dependent and independent mechanisms [15]. Aβ and NMDA receptor activation cause mitochondrial dysfunction involving ER Ca 2+ release [16]. These findings suggest a relevant role for Ca 2+ transfer from ER to mitochondria in neuron cell death.…”

An excessive increase in glutamate contributes to glucose-toxicity in β-cells via activation of pancreatic NMDA receptors in rodent diabetes

“…In the CNS, the excessive activation of NMDARs leads to oxidative damage38, occurring along with increased ROS production and causing excitatory neurotoxicity in neurons39. Several lines of evidence indicate that NMDARs also play an important role in regulating inflammation in neuronal and non-neuronal tissues, such as pulmonary inflammation1718.…”

RyR2-Mediated Ca2+ Release and Mitochondrial ROS Generation Partake in the Synaptic Dysfunction Caused by Amyloid β Peptide Oligomers

“…Furthermore, treatment with 500 nM AβOs increases reactive oxygen species (ROS) levels (De Felice et al, 2007; Lobos et al, 2016), decreases non-transferrin-bound iron uptake (SanMartín et al, 2012b) and induces differential gene expression (Sebollela et al, 2012). Addition of 500 nM AβOs increases cytoplasmic calcium in primary hippocampal (Paula-Lima et al, 2011) and cortical neurons (Ferreira et al, 2014) and cerebellar granule cells (Sanz-Blasco et al, 2008), and results in depolarization of mitochondrial membrane potential in primary cortical neurons (Ferreira et al, 2014) and cerebellar granule cells (Sanz-Blasco et al, 2008), among other effects. Moreover and closely related to our present results, 800 nM AβOs induce loss of dendritic spines and promote mitochondrial fission in rat hippocampal primary cultures (Wang et al, 2009).…”