Browsing by Author "von Bernhardi, Rommy"

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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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    Prenatal to Early Postnatal Nicotine Exposure Impairs Central Chemoreception and Modifies Breathing Pattern in Mouse Neonates: A Probable Link to Sudden Infant Death Syndrome
    (SOC NEUROSCIENCE, 2008) Eugenin, Jaime; Otarola, Marcelo; Bravo, Eduardo; Coddou, Claudio; Cerpa, Veronica; Reyes Parada, Miguel; Llona, Isabel; von Bernhardi, Rommy
    Nicotine is a neuroteratogen and is the likely link between maternal cigarette smoking during pregnancy and sudden infant death syndrome (SIDS). Osmotic minipumps were implanted in 5-7 d CF1 pregnant mice to deliver nicotine bitartrate (60 mg Kg(-1) day(-1)) or saline (control) solutions for up to 28 d. Prenatal to early postnatal nicotine exposure did not modify the number of newborns per litter or their postnatal growth; however, nicotine-exposed neonates hypoventilated and had reduced responses to hypercarbia (inhalation of air enriched with 10% CO2 for 20 min) and hypoxia (inhalation of 100% N-2 for 20 s) at postnatal days 0-3 (P0-P3). In contrast, at postnatal day 8, nicotine-exposed neonates were indistinguishable from controls. Isolated brainstem-spinal cord preparations obtained from P0 to P3 nicotine-exposed neonates showed fictive respiration with respiratory cycles longer and more irregular than those of controls, as indicated by high short- and long-term variability in Poincare plots. In addition, their responses to acidification were reduced, indicating compromise of central chemoreception. Furthermore, the cholinergic contribution to central chemosensory responses switched from muscarinic receptor to nicotinic receptor-based mechanisms. No significant astrogliosis was detectable in the ventral respiratory group of neurons with glial fibrillary acidic protein immunohistochemistry. These results indicate that nicotine exposure affects the respiratory rhythm pattern generator and causes a decline in central chemoreception during early postnatal life. Consequently, breathing would become highly vulnerable, failing to respond to chemosensory demands. Such impairment could be related to the ventilatory abnormalities observed in SIDS.
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    Proinflammatory stimuli are needed for induction of microglial cell-mediated A beta PP244-C and A beta-neurotoxicity in hippocampal cultures
    (IOS PRESS, 2008) Ramirez, Gigliola; Rey, Sergio; von Bernhardi, Rommy
    Amyloid-beta plaques and neurodegeneration are hallmarks of Alzheimer's disease, where glial cells are responsible for sustained neuroinflammation. Here we show that hippocampal-microglia co-cultures exposed to proinflammatory mediators, amyloid-beta- and amyloid-beta protein precursor construct-conjugated beads increased their production of nitrites. In contrast, inflammation was unable to significantly induce cell death by itself, whereas inflammation plus amyloid-beta or amyloid-beta protein precursor induced a significant increment of cell death and a 6-fold increase of production of Interleukin 1 beta. Those effects were not observed in the absence of microglia or when hippocampal cells were co-cultured with microglia for one day. In contrast, a 2-fold increase of transforming growth factor beta 1 was observed in hippocampal cultures exposed to inflammatory stimuli for 4 days, whereas induction of transforming growth factor beta 1 by inflammation plus amyloid-beta and amyloid-beta protein precursor was nearly abolished by microglia. Our results indicate that neurotoxicity induced by amyloid-beta or amyloid-beta protein precursor was a slow process depending on activated microglia and additional stimuli. The observed cytotoxicity could be consequence of a vicious cycle in which elevated concentrations of Interleukin 1 beta and radical species along with decreased secretion of neuroprotective cytokines such as transforming growth factor beta 1 support persistent activation of glial cells and cell damage.
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    Proliferating culture of aged microglia for the study of neurodegenerative diseases
    (2011) von Bernhardi, Rommy; Tichauer, Juan; Eugenin-von Bernhardi, Laura
    Microglial cells' phenotype and function change with aging. Since microglial cell impairments that are relevant for neurodegenerative diseases appear to be unique to aged individuals, it is important to assess function of aged microglia. However, most studies are done with microglia from neonates, mostly due to lack of reliable protocols to obtain microglia from adult animals. Here, we present a conditioned media-dependent culture system that promotes proliferation of adult microglia. We observed that inflammatory activation was increasingly oxidative in microglia from aged animals. Also, whereas phagocytosis of A beta by microglia from adult animals was more robust than that of microglia from neonates, the induction of phagocytosis by TGF beta was abolished in aged animals. Our results show the importance of using adult animals cells for the study of neurodegenerative processes or other diseases associated with aging. The proposed culture method is inexpensive and cell yield allows for their assessment by functional bioassays and biochemistry. (C) 2011 Elseviel B.V. All rights reserved.
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    The effect of aged microglia on synaptic impairment and its relevance in neurodegenerative diseases
    (2021) Jose Trivino, Juan; von Bernhardi, Rommy
    Microglia serve key functions in the central nervous system (CNS), participating in the establishment and regulation of synapses and the neuronal network, and regulating activity-dependent plastic changes. As the neuroimmune system, they respond to endogenous and exogenous signals to protect the CNS. In aging, one of the main changes is the establishment of inflamm-aging, a mild chronic inflammation that reduces microglial response to stressors. Neuroinflammation depends mainly on the increased activation of microglia. Microglia over-activation may result in a reduced capacity for performing normal functions related to migration, clearance, and the adoption of an anti-inflammatory state, contributing to an increased susceptibility for neurodegeneration. Oxidative stress contributes both to aging and to the progression of neurodegenerative diseases. Increased production of reactive oxygen species (ROS) and neuroinflammation associated with age-and disease dependent mechanisms affect synaptic activity and neurotransmission, leading to cognitive dysfunction. Astrocytes prevent microglial cell cytotoxicity by mechanisms mediated by transforming growth factor 131 (TGF131). However, TGF131-Smad3 pathway is impaired in aging, and the age-related impairment of TGF13 signaling can reduce protective activation while facilitating cytotoxic activation of microglia. A critical analysis on the effect of aging microglia on neuronal function is relevant for the understanding of age-related changes on neuronal function. Here, we present evidence in the context of the ?microglial dysregulation hypothesis?, which leads to the reduction of the protective functions and increased cytotoxicity of microglia, to discuss the mechanisms involved in neurodegenerative changes and Alzheimer?s disease.
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    Transforming growth factor-β stimulates β amyloid uptake by microglia through Smad3-dependent mechanisms
    (2012) Tichauer, Juan E.; von Bernhardi, Rommy
    Inflammatory cytokines and beta amyloid (A beta) induce activation of glial cells, leading to both protective and deleterious changes that are relevant for the pathogenesis of Alzheimer disease (AD). We have shown that astrocytes downregulate microglial cell cytotoxic activation through secretion of transforming growth factor-beta (TGF beta 1), and there is evidence that TGF beta 1 modifies A beta removal through the modulation of microglia. However, inflammatory activation of microglia is increased and A beta clearance is reduced in AD patients, regardless of the fact that TGF beta 1 is increased in their nervous system. We propose that changes in TGF beta Smad3 signal transduction could modify the regulation mediated by TGF beta 1. Here we evaluated the participation of the TGF beta Smad3 pathway in regulation of the expression pattern of scavenger receptors (SR) and activation of microglia through nitric oxide (NO.) secretion and phagocytosis of A beta. We found that TGF beta 1 increased SR-A by 2.4-fold and decreased SR-BI expression by 79% at 48 hr, whereas it did not change SR-MARCO or CD36 expression. In addition, we observed a 51% increase of A beta uptake and an 83% decrease of NO. production induced by lipopolysaccharide in microglial cell cultures. Increased expression of SR-A, phagocytosis, and downregulation of NO. by TGF beta 1 were prevented by the inhibition of the TGF beta Smad3 pathway. Our results indicate that the modulation of microglial cell activation by TGF beta 1, leading to increased clearance of A beta and reduced cytotoxicity, is at least partially mediated by the Smad pathway. (c) 2012 Wiley Periodicals, Inc.