Browsing by Author "Godoy, Juan A."

Now showing 1 - 13 of 13
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    Age Progression of Neuropathological Markers in the Brain of the Chilean Rodent Octodon degus, a Natural Model of Alzheimer's Disease
    (2015) Inestrosa Cantín, Nibaldo; Rios, Juvenal A.; Cisternas, Pedro; Tapia Rojas, Cheril Cecilia; Rivera, Daniela S.; Braidy, Nady; Zolezzi, Juan M.; Godoy, Juan A.; Carvajal Cachaña, Francisco Javier; Ardiles, Alvaro O.
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    Amyloid-B-Acetylcholinesterase complexes potentiate neurodegenerative changes induced by the AB peptide. Implications for the pathogenesis of Alzheimer's disease
    (2010) Dinamarca Ceballos, Margarita Constanza.; Sagal, Juan P.; Quintanilla Gómez, Rodrigo Arthur; Godoy, Juan A.; Arrázola, Macarena S; Inestrosa Cantín, Nibaldo
    Abstract The presence of amyloid-β (Aβ) deposits in selected brain regions is a hallmark of Alzheimer's disease (AD). The amyloid deposits have "chaperone molecules" which play critical roles in amyloid formation and toxicity. We report here that treatment of rat hippocampal neurons with Aβ-acetylcholinesterase (Aβ-AChE) complexes induced neurite network dystrophia and apoptosis. Moreover, the Aβ-AChE complexes induced a sustained increase in intracellular Ca2+ as well as a loss of mitochondrial membrane potential. The Aβ-AChE oligomers complex also induced higher alteration of Ca2+ homeostasis compared with Aβ-AChE fibrillar complexes. These alterations in calcium homeostasis were reversed when the neurons were treated previously with lithium, a GSK-3β inhibitor; Wnt-7a ligand, an activator for Wnt Pathway; and an N-methyl-D-aspartate (NMDA) receptor antagonist (MK-801), demonstrating protective roles for activation of the Wnt signaling pathway as well as for NMDA-receptor inhibition. Our results indicate that the Aβ-AChE complexes enhance Aβ-dependent deregulation of intracellular Ca2+ as well as mitochondrial dysfunction in hippocampal neurons, triggering an enhanced damage than Aβ alone. From a therapeutic point of view, activation of the Wnt signaling pathway, as well as NMDAR inhibition may be important factors to protect neurons under Aβ-AChE attack.
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    Amyloid-beta Peptide Nitrotyrosination Stabilizes Oligomers and Enhances NMDAR-Mediated Toxicity
    (2016) Guivernau, Biuse; Bonet, Jaume; Valls Comamala, Victoria; Bosch Morato, Mónica; Godoy, Juan A.; Inestrosa Cantín, Nibaldo
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    Emerging role of Metformin in Alzheimer's disease: A translational view
    (2024) Rios, Juvenal A.; Borquez, Juan Carlos; Godoy, Juan A.; Zolezzi, Juan M.; Furrianca, Maria Cristina; Inestrosa, Nibaldo C.
    Alzheimer's disease (AD) constitutes a major public-health issue of our time. Regrettably, despite our considerable understanding of the pathophysiological aspects of this disease, current interventions lead to poor outcomes. Furthermore, experimentally promising compounds have continuously failed when translated to clinical trials. Along with increased population ageing, Type 2 Diabetes Mellitus (T2DM) has become an extremely common condition, mainly due to unbalanced dietary habits. Substantial epidemiological evidence correlates T2DM with cognitive impairment as well. Considering that brain insulin resistance, mitochondrial dysfunction, oxidative stress, and amyloidogenesis are common phenomena, further approaching the common features among these pathological conditions. Metformin constitutes the first-choice drug to preclude insulin resistance in T2DM clinical management. Experimental evidence suggests that its functions might include neuroprotective effects, in addition to its hypoglycemic activity. This review aims to summarize and discuss current knowledge of experimental data on metformin on this path towards translational medicine. Finally, we discuss the controversial data of responses to metformin in vitro, and in vivo, animal models and human studies.
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    Peroxisome Proliferator-Activated Receptor (PPAR) γ and PPARα Agonists Modulate Mitochondrial Fusion-Fission Dynamics: Relevance to Reactive Oxygen Species (ROS)-Related Neurodegenerative Disorders?
    (2013) Zolezzi, Juan M.; Silva-Alvarez, Carmen; Ordenes, Daniela; Godoy, Juan A.; Carvajal, Francisco J.; Santos, Manuel J.; Inestrosa, Nibaldo C.
    Recent studies showed that the activation of the retinoid X receptor, which dimerizes with peroxisome proliferator-activated receptors (PPARs), leads to an enhanced clearance of A beta from the brain of transgenic mice model of Alzheimer's disease (AD), because an increased expression of apolipoprotein E and it main transporters. However, the effects observed must involve additional underlying mechanisms that have not been yet explored. Several studies conducted in our laboratory suggest that part of the effects observed for the PPARs agonist might involves mitochondrial function and, particularly, mitochondrial dynamics. In the present study we assessed the effects of oxidative stress challenge on mitochondrial morphology and mitochondrial dynamics-related proteins in hippocampal neurons. Using immunofluorescence, we evaluated the PPAR gamma co-activator 1 alpha (PGC-1 alpha), dynamin related protein 1 (DRP1), mitochondrial fission protein 1 (FIS1), and mitochondrial length, in order to determine if PPARs agonist pre-treatment is able to protect mitochondrial population from hippocampal neurons through modulation of the mitochondrial fusion-fission events. Our results suggest that both a PPAR gamma agonist (ciglitazone) and a PPAR alpha agonist (WY 14.643) are able to protect neurons by modulating mitochondrial fusion and fission, leading to a better response of neurons to oxidative stress, suggesting that a PPAR based therapy could acts simultaneously in different cellular components. Additionally, our results suggest that PGC-1 alpha and mitochondrial dynamics should be further studied in future therapy research oriented to ameliorate neurodegenerative disorders, such as AD.
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    Phosphorylated tau potentiates Aβ-induced mitochondrial damage in mature neurons
    (2014) Quintanilla, Rodrigo A.; von Bernhardi, Rommy; Godoy, Juan A.; Inestrosa, Nibaldo C.; Johnson, Gail V. W.
    Tau phosphorylated at the PHF-1 epitope (S396/S404) is likely involved in the pathogenesis of Alzheimer's disease (AD). However, the molecular mechanisms by which tau phosphorylated at these sites negatively impacts neuronal functions are still under scrutiny. Previously, we showed that expression of tau truncated at D421 enhances mitochondrial dysfunction induced by A beta in cortical neurons. To extend these findings, we expressed tau pseudo-phosphorylated at S396/404 (T42EC) in mature and young cortical neurons and evaluated different aspects of mitochondrial function in response to A beta. Expression of T42EC did not induce significant changes in mitochondrial morphology, mitochondrial length, or mitochondrial transport, compared to GFP and full-length tau. However, T42EC expression enhanced A beta-induced mitochondrial membrane potential loss and increased superoxide levels compared to what was observed in mature neurons expressing full-length tau. The same effect was observed in mature neurons that expressed both pseudo-phosphorylated and truncated tau when they were treated with AS. Interestingly, the mitochondrial failure induced by A beta in mature neurons that expressed T42EC, was not observed in young neurons expressing T42EC. These novel findings suggest that phosphorylated tau (PHF-1 epitope) enhances A beta-induced mitochondrial injury, which contributes to neuronal dysfunction and to the pathogenesis of AD. (C) 2014 Elsevier Inc All rights reserved.
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    PPARs in the central nervous system: roles in neurodegeneration and neuroinflammation
    (2017) Zolezzi, Juan M.; Santos Alcántara, Manuel; Bastías Candia, Sussy; Pinto, Claudio; Godoy, Juan A.; Inestrosa Cantín, Nibaldo
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    Quercetin Exerts Differential Neuroprotective Effects Against H2O2 and A beta Aggregates in Hippocampal Neurons: the Role of Mitochondria
    (2017) Godoy, Juan A.; Lindsay, Carolina B.; Quintanilla, Rodrigo A.; Carvajal Cachaña, Francisco Javier; Cerpa Nebott, Waldo Francisco; Inestrosa Cantín, Nibaldo
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    Serine-Arginine Protein Kinase SRPK2 Modulates the Assembly of the Active Zone Scaffolding Protein CAST1/ERC2
    (2019) Arancibia, Duxan; Lira, Matias; Cruz, Yocelin; Barrera, Daniela P.; Montenegro-Venegas, Carolina; Godoy, Juan A.; Garner, Craig C.; Inestrosa, Nibaldo C.; Gundelfinger, Eckart D.; Zamorano, Pedro; Torres, Viviana, I
    Neurons release neurotransmitters at a specialized region of the presynaptic membrane, the active zone (AZ), where a complex meshwork of proteins organizes the release apparatus. The formation of this proteinaceous cytomatrix at the AZ (CAZ) depends on precise homo- and hetero-oligomerizations of distinct CAZ proteins. The CAZ protein CAST1/ERC2 contains four coiled-coil (CC) domains that interact with other CAZ proteins, but also promote self-assembly, which is an essential step for its integration during AZ formation. The self-assembly and synaptic recruitment of the Drosophila protein Bruchpilot (BRP), a partial homolog of CAST1/ERC2, is modulated by the serine-arginine protein kinase (SRPK79D). Here, we demonstrate that overexpression of the vertebrate SRPK2 regulates the self-assembly of CAST1/ERC2 in HEK293T, SH-SY5Y and HT-22 cells and the CC1 and CC4 domains are involved in this process. Moreover, the isoform SRPK2 forms a complex with CAST1/ERC2 when co-expressed in HEK293T and SH-SY5Y cells. More importantly, SRPK2 is present in brain synaptic fractions and synapses, suggesting that this protein kinase might control the level of self-aggregation of CAST1/ERC2 in synapses, and thereby modulate presynaptic assembly.
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    SIRT1 Regulates Dendritic Development in Hippocampal Neurons
    (2012) Codocedo, Juan F.; Allard, Claudio; Godoy, Juan A.; Varela-Nallar, Lorena; Inestrosa, Nibaldo C.
    Dendritic arborization is required for proper neuronal connectivity. SIRT1, a NAD+ dependent histone deacetylase, has been associated to ageing and longevity, which in neurons is linked to neuronal differentiation and neuroprotection. In the present study, the role of SIRT1 in dendritic development was evaluated in cultured hippocampal neurons which were transfected at 3 days in vitro with a construct coding for SIRT1 or for the dominant negative SIRT1H363Y, which lacks the catalytic activity. Neurons overexpressing SIRT1 showed an increased dendritic arborization, while neurons overexpressing SIRT1H363Y showed a reduction in dendritic arbor complexity. The effect of SIRT1 was mimicked by treatment with resveratrol, a well known activator of SIRT1, which has no effect in neurons overexpressing SIRT1H363Y indicating that the effect of resveratrol was specifically mediated by SIRT1. Moreover, hippocampal neurons overexpressing SIRT1 were resistant to dendritic dystrophy induced by A beta aggregates, an effect that was dependent on the deacetylase activity of SIRT1. Our findings indicate that SIRT1 plays a role in the development and maintenance of dendritic branching in hippocampal neurons, and suggest that these effects are mediated by the ROCK signaling pathway.
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    Tetrahydrohyperforin Induces Mitochondrial Dynamics and Prevents Mitochondrial Ca2+ Overload after Aβ and Aβ-AChE Complex Challenge in Rat Hippocampal Neurons
    (2013) Zolezzi, Juan M.; Carvajal, Francisco J.; Rios, Juvenal A.; Ordenes, Daniela; Silva-Alvarez, C.; Godoy, Juan A.; Inestrosa, Nibaldo C.
    St. John's wort has been the subject of studies focused on its therapeutic properties against several diseases, including Alzheimer's disease (AD). Amyloid beta-peptide (A beta), a critical peptide in AD, has been linked to the mitochondrial dysfunction often observed in this disease. Despite many efforts to prevent A beta levels from increasing in AD, less has been done regarding the mitochondrial component. Therefore, we studied the effects of tetrahydrohyperforin (THH) on mitochondrial dysfunction of hippocampal neurons, challenged with A beta oligomers (A beta o) and A beta o-AChE complexes. We show that THH prevents mitochondrial calcium overload and induces the modulation of fusion-fission events, arresting mitochondrial dysfunction. Moreover, our results suggest that the modulation of mitochondrial dynamics probably occurs through a peroxisome proliferator-activated receptor gamma co-activator 1 alpha-mediated mechanism, inducing mitochondrial fusion-fission protein expression. Our results offer further explanation for the effects observed for THH and the beneficial effects of this ethno-botanical drug in AD.
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    The soluble extracellular fragment of neuroligin-1 targets Aβ oligomers to the postsynaptic region of excitatory synapses
    (2015) Dinamarca, Margarita C.; Di Luca, Mónica; Godoy, Juan A.; Inestrosa Cantín, Nibaldo
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    Wnt5a inhibits K+ currents in hippocampal synapses through nitric oxide production
    (2015) Parodi, Jorge; Montecinos Oliva, Carla; Varas, Rodrigo; Alfaro, Iván E.; Serrano, Felipe G.; Varas Godoy, Manuel; Muñoz, Francisco J.; Cerpa Nebott, Waldo Francisco; Godoy, Juan A.; Inestrosa Cantín, Nibaldo