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1.
J Neurochem ; 2024 Sep 12.
Artículo en Inglés | MEDLINE | ID: mdl-39263896

RESUMEN

Amyloid-beta peptide oligomers (AßO) have been considered "primum movens" for a cascade of events that ultimately cause selective neuronal death in Alzheimer's disease (AD). However, initial events triggered by AßO have not been clearly defined. Synaptic (Syn) N-methyl-d-aspartate receptors (NMDAR) are known to activate cAMP response element-binding protein (CREB), a transcriptional factor involved in gene expression related to cell survival, memory formation and synaptic plasticity, whereas activation of extrasynaptic (ESyn) NMDARs was linked to excitotoxic events. In AD brain, CREB phosphorylation/activation was shown to be altered, along with dyshomeostasis of intracellular Ca2+ (Ca2+ i). Thus, in this work, we analyze acute/early and long-term AßO-mediated changes in CREB activation involving Syn or ESyn NMDARs in mature rat cortical neurons. Our findings show that acute AßO exposure produce early increase in phosphorylated CREB, reflecting CREB activity, in a process occurring through Syn NMDAR-mediated Ca2+ influx. Data also demonstrate that AßO long-term (24 h) exposure compromises synaptic function related to Ca2+-dependent CREB phosphorylation/activation and nuclear CREB levels and related target genes, namely Bdnf, Gadd45γ, and Btg2. Data suggest a dual effect of AßO following early or prolonged exposure in mature cortical neurons through the activation of the CREB signaling pathway, linked to the activation of Syn NMDARs.

2.
Front Mol Neurosci ; 11: 328, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-30271322

RESUMEN

Synaptic scaling is a form of homeostatic plasticity that is critical for maintaining neuronal activity within a dynamic range, and which alters synaptic strength through changes in postsynaptic AMPA-type glutamate receptors. Homeostatic scaling down of excitatory synapses has been shown to occur during sleep, and to contribute to synapse remodeling and memory consolidation, but the underlying mechanisms are only partially known. Here, we report that synaptic downscaling in cortical neurons is accompanied by dephosphorylation of the transmembrane AMPA receptor regulatory protein stargazin, and by an increase in its cell surface mobility. The changes in stargazin surface diffusion were paralleled by an increase in the mobility of GluA1-containing AMPA receptors at synaptic sites. In addition, stargazin dephosphorylation was required for the downregulation of surface levels of GluA1-containing AMPA receptors promoted by chronic elevation of neuronal activity, specifically by mediating the interaction with the adaptor proteins AP-2 and AP-3A. Disruption of the stargazin-AP-3A interaction was sufficient to prevent the decrease in cell surface GluA1-AMPA receptor levels associated with chronically enhanced synaptic activity, suggesting that scaling down is accomplished through decreased AMPA receptor recycling and enhanced lysosomal degradation. Thus, synaptic downscaling is associated with both increased stargazin and AMPA receptor cell surface diffusion, as well as with stargazin-mediated AMPA receptor endocytosis and lysosomal degradation.

3.
Mol Neurobiol ; 54(7): 5385-5399, 2017 09.
Artículo en Inglés | MEDLINE | ID: mdl-27590140

RESUMEN

Sirtuin 1 (SIRT1) is a nicotinamide adenine dinucleotide (NAD+)-dependent lysine deacetylase that regulates longevity and enhances mitochondrial metabolism. Both activation and inhibition of SIRT1 were previously shown to ameliorate neuropathological mechanisms in Huntington's disease (HD), a neurodegenerative disease that selectively affects the striatum and cortex and is commonly linked to mitochondrial dysfunction. Thus, in this study, we tested the influence of resveratrol (RESV, a SIRT1 activator) versus nicotinamide (NAM, a SIRT1 inhibitor) in counteracting mitochondrial dysfunction in HD models, namely striatal and cortical neurons isolated from YAC128 transgenic mice embryos, HD human lymphoblasts, and an in vivo HD model. HD cell models displayed a deregulation in mitochondrial membrane potential and respiration, implicating a decline in mitochondrial function. Further studies revealed decreased PGC-1α and TFAM protein levels, linked to mitochondrial DNA loss in HD lymphoblasts. Remarkably, RESV completely restored these parameters, while NAM increased NAD+ levels, providing a positive add on mitochondrial function in in vitro HD models. In general, RESV decreased while NAM increased H3 acetylation at lysine 9. In agreement with in vitro data, continuous RESV treatment for 28 days significantly improved motor coordination and learning and enhanced expression of mitochondrial-encoded electron transport chain genes in YAC128 mice. In contrast, high concentrations of NAM blocked mitochondrial-related transcription, worsening motor phenotype. Overall, data indicate that activation of deacetylase activity by RESV improved gene transcription associated to mitochondrial function in HD, which may partially control HD-related motor disturbances.


Asunto(s)
Enfermedad de Huntington/genética , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Niacinamida/farmacología , Estilbenos/farmacología , Animales , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , ADN Mitocondrial/metabolismo , Modelos Animales de Enfermedad , Humanos , Ratones Transgénicos , Mitocondrias/metabolismo , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Resveratrol
4.
Biochim Biophys Acta ; 1852(7): 1428-41, 2015 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-25857617

RESUMEN

Oxidative stress and endoplasmic reticulum (ER) stress have been associated with Alzheimer's disease (AD) progression. In this study we analyzed whether oxidative stress involving changes in Nrf2 and ER stress may constitute early events in AD pathogenesis by using human peripheral blood cells and an AD transgenic mouse model at different disease stages. Increased oxidative stress and increased phosphorylated Nrf2 (p(Ser40)Nrf2) were observed in human peripheral blood mononuclear cells (PBMCs) isolated from individuals with mild cognitive impairment (MCI). Moreover, we observed impaired ER Ca2+ homeostasis and increased ER stress markers in PBMCs from MCI individuals and mild AD patients. Evidence of early oxidative stress defense mechanisms in AD was substantiated by increased p(Ser40)Nrf2 in 3month-old 3xTg-AD male mice PBMCs, and also with increased nuclear Nrf2 levels in brain cortex. However, SOD1 protein levels were decreased in human MCI PBMCs and in 3xTg-AD mice brain cortex; the latter further correlated with reduced SOD1 mRNA levels. Increased ER stress was also detected in the brain cortex of young female and old male 3xTg-AD mice. We demonstrate oxidative stress and early Nrf2 activation in AD human and mouse models, which fails to regulate some of its targets, leading to repressed expression of antioxidant defenses (e.g., SOD-1), and extending to ER stress. Results suggest markers of prodromal AD linked to oxidative stress associated with Nrf2 activation and ER stress that may be followed in human peripheral blood mononuclear cells.


Asunto(s)
Enfermedad de Alzheimer/metabolismo , Estrés del Retículo Endoplásmico , Factor 2 Relacionado con NF-E2/metabolismo , Estrés Oxidativo , Anciano , Anciano de 80 o más Años , Animales , Células Cultivadas , Corteza Cerebral/crecimiento & desarrollo , Corteza Cerebral/metabolismo , Disfunción Cognitiva/metabolismo , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , ARN Mensajero/genética , ARN Mensajero/metabolismo , Superóxido Dismutasa/genética , Superóxido Dismutasa/metabolismo , Superóxido Dismutasa-1
5.
J Alzheimers Dis ; 34(1): 115-31, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23364141

RESUMEN

Alzheimer's disease (AD) is the major cause of dementia in the world. Abnormal extracellular accumulation of amyloid-ß (Aß) peptide and tau hyperphosphorylation, forming neurofibrillary tangles in the brain, are hallmarks of the disease. Oxidative stress, neuroinflammation, and mitochondrial and synaptic dysfunction are also observed in AD and often correlated to intracellular Aß. This peptide results from the cleavage of the amyloid-ß protein precursor by ß- and γ-secretases and tends to be secreted after its production. However, secreted Aß can be internalized by the interaction with membrane receptors, namely N-methyl-D-aspartate receptors, advanced glycation end products receptors, and/or alpha 7 nicotinic acetylcholine receptors. Inside the cell, Aß interacts with several organelles, including mitochondria and nucleus, and there is growing evidence pointing to a possible role of Aß in the regulation of gene transcription. Accordingly, transcriptional deregulation was observed in several AD models and human samples from AD patients through modified expression, phosphorylation levels, function, and subcellular localization of some transcription factors, resulting in the suppression of neuroprotective transcription both in the nucleus and the mitochondria. In this review we focus on key transcription regulators related with mitochondrial biogenesis and antioxidant defenses that seem to be altered in AD models and also on the role of intranuclear Aß in the pathogenesis of the disease.


Asunto(s)
Enfermedad de Alzheimer/complicaciones , Regulación de la Expresión Génica/fisiología , Enfermedades Mitocondriales/etiología , Estrés Oxidativo/fisiología , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Animales , Humanos , Mitocondrias/patología , Proteínas tau/metabolismo
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