Browsing by Author "Munoz, Francisco J."

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    Amyloid β-Peptide Causes the Permanent Activation of CaMKIIα through Its Oxidation
    (2022) Picon-Pages, Pol; Fanlo-Ucar, Hugo; Herrera-Fernandez, Victor; Auselle-Bosch, Sira; Galera-Lopez, Lorena; Gutierrez, Daniela A.; Ozaita, Andres; Alvarez, Alejandra R.; Oliva, Baldomero; Munoz, Francisco J.
    Alzheimer's disease (AD) is characterised by the presence of extracellular amyloid plaques in the brain. They are composed of aggregated amyloid beta-peptide (A beta) misfolded into beta-sheets which are the cause of the AD memory impairment and dementia. Memory depends on the hippocampal formation and maintenance of synapses by long-term potentiation (LTP), whose main steps are the activation of NMDA receptors, the phosphorylation of CaMKII alpha and the nuclear translocation of the transcription factor CREB. It is known that A beta oligomers (oA beta) induce synaptic loss and impair the formation of new synapses. Here, we have studied the effects of oA beta on CaMKII alpha. We found that oA beta produce reactive oxygen species (ROS), that induce CaMKII alpha oxidation in human neuroblastoma cells as we assayed by western blot and immunofluorescence. Moreover, this oxidized isoform is significantly present in brain samples from AD patients. We found that the oxidized CaMKII alpha is active independently of the binding to calcium/calmodulin, and that CaMKII alpha phosphorylation is mutually exclusive with CaMKII alpha oxidation as revealed by immunoprecipitation and western blot. An in silico modelling of the enzyme was also performed to demonstrate that oxidation induces an activated state of CaMKII alpha. In brains from AD transgenic models of mice and in primary cultures of murine hippocampal neurons, we demonstrated that the oxidation of CaMKII alpha induces the phosphorylation of CREB and its translocation to the nucleus to promote the transcription of ARC and BDNF. Our data suggests that CaMKII alpha oxidation would be a pro-survival mechanism that is triggered when a noxious stimulus challenges neurons as do oA beta.
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    Physiological Control of Nitric Oxide in Neuronal BACE1 Translation by Heme-Regulated eIF2α Kinase HRI Induces Synaptogenesis
    (2015) ILL-Raga, Gerard; Tajes, Marta; Busquets-Garcia, Arnau; Ramos-Fernandez, Eva; Vargas, Lina M.; Bosch-Morato, Monica; Guivernau, Biuse; Valls-Comamala, Victoria; Eraso-Pichot, Abel; Guix, Francesc X.; Fandos, Cesar; Rosen, Mark D.; Rabinowitz, Michael H.; Maldonado, Rafael; Alvarez, Alejandra R.; Ozaita, Andres; Munoz, Francisco J.
    Aims: Hippocampus is the brain center for memory formation, a process that requires synaptogenesis. However, hippocampus is dramatically compromised in Alzheimer's disease due to the accumulation of amyloid beta-peptide, whose production is initiated by beta-site APP Cleaving Enzyme 1 (BACE1). It is known that pathological stressors activate BACE1 translation through the phosphorylation of the eukaryotic initiation factor-2 alpha (eIF2 alpha) by GCN2, PERK, or PKR kinases, leading to amyloidogenesis. However, BACE1 physiological regulation is still unclear. Since nitric oxide (NO) participates directly in hippocampal glutamatergic signaling, we investigated the neuronal role of the heme-regulated eukaryotic initiation factor eIF2 alpha kinase (HRI), which can bind NO by a heme group, in BACE1 translation and its physiological consequences. Results: We found that BACE1 is expressed on glutamate activation with NO being the downstream effector by triggering eIF2 alpha phosphorylation, as it was obtained by Western blot and luciferase assay. It is due to the activation of HRI by NO as assayed by Western blot and immunofluorescence with an HRI inhibitor and HRI siRNA. BACE1 expression was early detected at synaptic spines, contributing to spine growth and consolidating the hippocampal memory as assayed with mice treated with HRI or neuronal NO synthase inhibitors. Innovation: We provide the first description that HRI and eIF2 alpha are working in physiological conditions in the brain under the control of nitric oxide and glutamate signaling, and also that BACE1 has a physiological role in hippocampal function. Conclusion: We conclude that BACE1 translation is controlled by NO through HRI in glutamatergic hippocampal synapses, where it plays physiological functions, allowing the spine growth and memory consolidation. Antioxid. Redox Signal. 22, 1295-1307.