ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2012
A new concept: Aβ1-42 generates a hyperfunctional proteolytic NCX3 fragment that delays caspase-12 activation and neuronal death.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 43 papers.
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Who cites it
43 citing papers in PubMed, 71 citations in OpenAlex.
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- Dysregulation of Ion Channels and Transporters and Blood-Brain Barrier Dysfunction in Alzheimer's Disease and Vascular Dementia.Aging and disease · 2024Review
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- In Silico Analysis Reveals the Modulation of Ion Transmembrane Transporters in the Cerebellum of Alzheimer's Disease Patients.International journal of molecular sciences · 2023Article
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- Emerging Role of DREAM in Healthy Brain and Neurological Diseases.International journal of molecular sciences · 2023Review
- Astrocyte contribution to dysfunction, risk and progression in neurodegenerative disorders.Nature reviews. Neuroscience · 2023Review
- Internalized Amyloid-β (1-42) Peptide Inhibits the Store-Operated Calcium Entry in HT-22 Cells.International journal of molecular sciences · 2022Article
- Amyloid AβInternational journal of molecular sciences · 2022Article
- NaCell communication and signaling : CCS · 2022Article
- New Insights into the Structure-Activity Relationship and Neuroprotective Profile of Benzodiazepinone Derivatives ofJournal of medicinal chemistry · 2021Article
- Ncx3-Induced Mitochondrial Dysfunction in Midbrain Leads to Neuroinflammation in Striatum of A53t-α-Synuclein Transgenic Old Mice.International journal of molecular sciences · 2021Article
- The Antioxidant Activity of Limonene Counteracts Neurotoxicity Triggered byAβAntioxidants (Basel, Switzerland) · 2021Article
- Calcium Dyshomeostasis in Alzheimer's Disease Pathogenesis.International journal of molecular sciences · 2021Review
- The NaFrontiers in pharmacology · 2021Article
- HDAC4 and HDAC5 form a complex with DREAM that epigenetically down-regulates NCX3 gene and its pharmacological inhibition reduces neuronal stroke damage.Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism · 2020Article
- miR-206 Reduces the Severity of Motor Neuron Degeneration in the Facial Nuclei of the Brainstem in a Mouse Model of SMA.Molecular therapy : the journal of the American Society of Gene Therapy · 2020Article
- Gender Differences in Neurodegeneration, Neuroinflammation and NaFrontiers in aging neuroscience · 2020Article
- The dual face of glutamate: from a neurotoxin to a potential survival factor-metabolic implications in health and disease.Cellular and molecular life sciences : CMLS · 2019Review
Corrections and comments
- Erratum issuedSokolow, Sophie [added]; Herchuelz, André [added]
Authors and funding
13 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Although the amyloid-β(1-42) (Aβ(1-42)) peptide involved in Alzheimer's disease is known to cause a dysregulation of intracellular Ca(2+) homeostasis, its molecular mechanisms still remain unclear. We report that the extracellular-dependent early increase (30 min) in intracellular calcium concentration ([Ca(2+)](i)), following Aβ(1-42) exposure, caused the activation of calpain that in turn elicited a cleavage of the Na(+)/Ca(2+) exchanger isoform NCX3. This cleavage generated a hyperfunctional form of the antiporter and increased NCX currents (I(NCX)) in the reverse mode of operation. Interestingly, this NCX3 calpain-dependent cleavage was essential for the Aβ(1-42)-dependent I(NCX) increase. Indeed, the calpain inhibitor calpeptin and the removal of the calpain-cleavage recognition sequence, via site-directed mutagenesis, abolished this effect. Moreover, the enhanced NCX3 activity was paralleled by an increased Ca(2+) content in the endoplasmic reticulum (ER) stores. Remarkably, the silencing in PC-12 cells or the knocking-out in mice of the ncx3 gene prevented the enhancement of both I(NCX) and Ca(2+) content in ER stores, suggesting that NCX3 was involved in the increase of ER Ca(2+) content stimulated by Aβ(1-42). By contrast, in the late phase (72 h), when the NCX3 proteolytic cleavage abruptly ceased, the occurrence of a parallel reduction in ER Ca(2+) content triggered ER stress, as revealed by caspase-12 activation. Concomitantly, the late increase in [Ca(2+)](i) coincided with neuronal death. Interestingly, NCX3 silencing caused an earlier activation of Aβ(1-42)-induced caspase-12. Indeed, in NCX3-silenced neurons, Aβ(1-42) exposure hastened caspase-dependent apoptosis, thus reinforcing neuronal cell death. These results suggest that Aβ(1-42), through Ca(2+)-dependent calpain activation, generates a hyperfunctional form of NCX3 that, by increasing Ca(2+) content into ER, delays caspase-12 activation and thus neuronal death.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.