The DOI matches its Crossref record; 12 of the 12 references it cites were found in a registry or an index.
Mitochondrial Ca2+ Overload Underlies Aβ Oligomers Neurotoxicity Providing an Unexpected Mechanism of Neuroprotection by NSAIDs
Open accessAbstract
Dysregulation of intracellular Ca(2+) homeostasis may underlie amyloid beta peptide (Abeta) toxicity in Alzheimer's Disease (AD) but the mechanism is unknown. In search for this mechanism we found that Abeta(1-42) oligomers, the assembly state correlating best with cognitive decline in AD, but not Abeta fibrils, induce a massive entry of Ca(2+) in neurons and promote mitochondrial Ca(2+) overload as shown by bioluminescence imaging of targeted aequorin in individual neurons. Abeta oligomers induce also mitochondrial permeability transition, cytochrome c release, apoptosis and cell death. Mitochondrial depolarization prevents mitochondrial Ca(2+) overload, cytochrome c release and cell death. In addition, we found that a series of non-steroidal anti-inflammatory drugs (NSAIDs) including salicylate, sulindac sulfide, indomethacin, ibuprofen and R-flurbiprofen depolarize mitochondria and inhibit mitochondrial Ca(2+) overload, cytochrome c release and cell death induced by Abeta oligomers. Our results indicate that i) mitochondrial Ca(2+) overload underlies the neurotoxicity induced by Abeta oligomers and ii) inhibition of mitochondrial Ca(2+) overload provides a novel mechanism of neuroprotection by NSAIDs against Abeta oligomers and AD.
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Cites
Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid β-peptide
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Close Contacts with the Endoplasmic Reticulum as Determinants of Mitochondrial Ca 2+ Responses
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A subset of NSAIDs lower amyloidogenic Aβ42 independently of cyclooxygenase activity
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“. Some NSAIDs including R-flurbiprofen have been reported to target and inhibit γ-secretase activity at rather large concentrations (100 µM) leading to a lower Aβ burden”
BackgroundNonsteroidal Antiinflammatory Drugs and the Risk of Alzheimer's Disease
in 't Veld, B. A., Ruitenberg, A., Hofman, A., Launer, L. J., van Duijn, C. M., Stijnen, T., Breteler, M. M. B., & Stricker, B. H. C. (2001) · New England Journal of Medicine · doi:10.1056/nejmoa010178 · Cited by 1,196
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Assembly and aggregation properties of synthetic Alzheimer's A4/beta amyloid peptide analogs.
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Mitochondrial Aβ: a potential focal point for neuronal metabolic dysfunction in Alzheimer's disease
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NSAIDs and enantiomers of flurbiprofen target γ-secretase and lower Aβ42 in vivo
Eriksen, J. L., Sagi, S. A., Smith, T. E., Weggen, S., Das, P., McLendon, D. C., Ozols, V. V., Jessing, K. W., Zavitz, K. H., Koo, E. H., et al. (2003) · Journal of Clinical Investigation · doi:10.1172/jci18162 · Cited by 634
Cited by
Calcium signaling and neurodegenerative diseases
Bezprozvanny, I. (2009) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2009.01.001 · Cited by 469
Excitotoxicity, calcium and mitochondria: a triad in synaptic neurodegeneration
Verma, M., Lizama, B. N., & Chu, C. T. (2022) · Translational Neurodegeneration · doi:10.1186/s40035-021-00278-7 · Cited by 451
Mitochondrial calcium exchange in physiology and disease
Garbincius, J. F., & Elrod, J. W. (2022) · Physiological Reviews · doi:10.1152/physrev.00041.2020 · Cited by 412
Amyloid beta, mitochondrial structural and functional dynamics in Alzheimer's disease
Reddy, P. H. (2009) · Experimental Neurology · doi:10.1016/j.expneurol.2009.03.042 · Cited by 264
Mitochondria and Calcium in Alzheimer’s Disease: From Cell Signaling to Neuronal Cell Death
Calvo-Rodriguez, M., & Bacskai, B. J. (2021) · Trends in Neurosciences · doi:10.1016/j.tins.2020.10.004 · Cited by 254
Metadata
- Authors
- Sanz-Blasco, S., Valero, R. A., Rodríguez-Crespo, I., Villalobos, C., & Núñez, L.
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2008-07-23
- Volume
- 3
- Issue
- 7
- Pages
- e2718
- ISSN
- 1932-6203 (ISSN-L)
- OpenAlex
- W2026930283
- Cited by
- 219
- References
- 12
- FWCI
- 8.04
- Type
- journal article
- Language
- en
- Open access
- gold
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- Sanz-Blasco, S., Valero, R. A., Rodríguez-Crespo, I., Villalobos, C., & Núñez, L. (2008). Mitochondrial Ca2+ Overload Underlies Aβ Oligomers Neurotoxicity Providing an Unexpected Mechanism of Neuroprotection by NSAIDs. PLoS ONE. https://doi.org/10.1371/journal.pone.0002718
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