Browsing by Author "Inestrosa, Nibaldo C."

Now showing 1 - 14 of 14
  • No Thumbnail Available
    Item
    A Multivariate Assessment of Age-Related Cognitive Impairment in Octodon degus
    (2021) Rivera, Daniela S.; Lindsay, Carolina B.; Oliva, Carolina A.; Bozinovic, Francisco; Inestrosa, Nibaldo C.
    Aging is a progressive functional decline characterized by a gradual deterioration in physiological function and behavior. The most important age-related change in cognitive function is decline in cognitive performance (i.e., the processing or transformation of information to make decisions that includes speed of processing, working memory, and learning). The purpose of this study is to outline the changes in age-related cognitive performance (i.e., short-term recognition memory and long-term learning and memory) in long-lived Octodon degus. The strong similarity between degus and humans in social, metabolic, biochemical, and cognitive aspects makes it a unique animal model for exploring the mechanisms underlying the behavioral and cognitive deficits related to natural aging. In this study, we examined young adult female degus (12- and 24-months-old) and aged female degus (38-, 56-, and 75-months-old) that were exposed to a battery of cognitive-behavioral tests. Multivariate analyses of data from the Social Interaction test or Novel Object/Local Recognition (to measure short-term recognition memory), and the Barnes maze test (to measure long-term learning and memory) revealed a consistent pattern. Young animals formed a separate group of aged degus for both short- and long-term memories. The association between the first component of the principal component analysis (PCA) from short-term memory with the first component of the PCA from long-term memory showed a significant negative correlation. This suggests age-dependent differences in both memories, with the aged degus having higher values of long-term memory ability but poor short-term recognition memory, whereas in the young degus an opposite pattern was found. Approximately 5% of the young and 80% of the aged degus showed an impaired short-term recognition memory; whereas for long-term memory about 32% of the young degus and 57% of the aged degus showed decreased performance on the Barnes maze test. Throughout this study, we outlined age-dependent cognitive performance decline during natural aging in degus. Moreover, we also demonstrated that the use of a multivariate approach let us explore and visualize complex behavioral variables, and identified specific behavioral patterns that allowed us to make powerful conclusions that will facilitate further the study on the biology of aging. In addition, this study could help predict the onset of the aging process based on behavioral performance.
  • No Thumbnail Available
    Item
    Adiponectin and resistin modulate the progression of Alzheimer's disease in a metabolic syndrome model
    (2023) Cisternas, Pedro; Gherardelli, Camila; Gutierrez, Joel; Salazar, Paulina; Mendez-Orellana, Carolina; Wong, G. William; Inestrosa, Nibaldo C.
    Metabolic syndrome (MetS), a cluster of metabolic conditions that include obesity, hyperlipidemia, and insulin resistance, increases the risk of several aging-related brain diseases, including Alzheimer's disease (AD). However, the underlying mechanism explaining the link between MetS and brain function is poorly understood. Among the possible mediators are several adipose-derived secreted molecules called adipokines, including adiponectin (ApN) and resistin, which have been shown to regulate brain function by modulating several metabolic processes. To investigate the impact of adipokines on MetS, we employed a diet-induced model to induce the various complications associated with MetS. For this purpose, we administered a high-fat diet (HFD) to both WT and APP/PSN1 mice at a pre-symptomatic disease stage. Our data showed that MetS causes a fast decline in cognitive performance and stimulates A beta(42) production in the brain. Interestingly, ApN treatment restored glucose metabolism and improved cognitive functions by 50% while decreasing the A beta(42/40) ratio by approximately 65%. In contrast, resistin exacerbated Ab pathology, increased oxidative stress, and strongly reduced glucose metabolism. Together, our data demonstrate that ApN and resistin alterations could further contribute to AD pathology.
  • No Thumbnail Available
    Item
    Age-Dependent Behavioral and Synaptic Dysfunction Impairment Are Improved with Long-Term Andrographolide Administration in Long-Lived Female Degus (Octodon degus)
    (2023) Oliva, Carolina A.; Rivera, Daniela S.; Torres, Angie K.; Lindsay, Carolina B.; Tapia-Rojas, Cheril; Bozinovic, Francisco; Inestrosa, Nibaldo C.
    In Octodon degus, the aging process is not equivalent between sexes and worsens for females. To determine the beginning of detrimental features in females and the ways in which to improve them, we compared adult females (36 months old) and aged females (72 months old) treated with Andrographolide (ANDRO), the primary ingredient in Andrographis paniculata. Our behavioral data demonstrated that age does not affect recognition memory and preference for novel experiences, but ANDRO increases these at both ages. Sociability was also not affected by age; however, social recognition and long-term memory were lower in the aged females than adults but were restored with ANDRO. The synaptic physiology data from brain slices showed that adults have more basal synaptic efficiency than aged degus; however, ANDRO reduced basal activity in adults, while it increased long-term potentiation (LTP). Instead, ANDRO increased the basal synaptic activity and LTP in aged females. Age-dependent changes were also observed in synaptic proteins, where aged females have higher synaptotagmin (SYT) and lower postsynaptic density protein-95 (PSD95) levels than adults. ANDRO increased the N-methyl D-aspartate receptor subtype 2B (NR2B) at both ages and the PSD95 and Homer1 only in the aged. Thus, females exposed to long-term ANDRO administration show improved complex behaviors related to age-detrimental effects, modulating mechanisms of synaptic transmission, and proteins.
  • No Thumbnail Available
    Item
    Andrographolide promotes hippocampal neurogenesis and spatial memory in the APPswe/PS1ΔE9 mouse model of Alzheimer's disease
    (2021) Arredondo, Sebastian B.; Reyes, Daniel T.; Herrera-Soto, Andrea; Mardones, Muriel D.; Inestrosa, Nibaldo C.; Varela-Nallar, Lorena
    In Alzheimer ' s disease (AD) there is a reduction in hippocampal neurogenesis that has been associated to cognitive deficits. Previously we showed that Andrographolide (ANDRO), the main bioactive component of Andrographis paniculate, induces proliferation in the hippocampus of the APPswe/PSEN1 Delta E9 (APP/PS1) mouse model of AD as assessed by staining with the mitotic marker Ki67. Here, we further characterized the effect of ANDRO on hippocampal neurogenesis in APP/PS1 mice and evaluated the contribution of this process to the cognitive effect of ANDRO. Treatment of 8-month-old APP/PS1 mice with ANDRO for 4 weeks increased proliferation in the dentate gyrus as evaluated by BrdU incorporation. Although ANDRO had no effect on neuronal differentiation of newborn cells, it strongly increased neural progenitors, neuroblasts and newborn immature neurons, cell populations that were decreased in APP/PS1 mice compared to age-matched wild-type mice. ANDRO had no effect on migration or in total dendritic length, arborization and orientation of immature neurons, suggesting no effects on early morphological development of newborn neurons. Finally, ANDRO treatment improved the performance of APP/PS1 mice in the object location memory task. This effect was not completely prevented by co-treatment with the anti-mitotic drug TMZ, suggesting that other effects of ANDRO in addition to the increase in neurogenesis might underlie the observed cognitive improvement. Altogether, our data indicate that in APP/PS1 mice ANDRO stimulates neurogenesis in the hippocampus by inducing proliferation of neural precursor cells and improves spatial memory performance.
  • No Thumbnail Available
    Item
    Cardiovascular and autonomic dysfunction in long-COVID syndrome and the potential role of non-invasive therapeutic strategies on cardiovascular outcomes
    (2023) Allendes, Francisca J.; Diaz, Hugo S.; Ortiz, Fernando C.; Marcus, Noah J.; Quintanilla, Rodrigo; Inestrosa, Nibaldo C.; Del Rio, Rodrigo
    A significant percentage of COVID-19 survivors develop long-lasting cardiovascular sequelae linked to autonomic nervous system dysfunction, including fatigue, arrhythmias, and hypertension. This post-COVID-19 cardiovascular syndrome is one facet of "long-COVID," generally defined as long-term health problems persisting/appearing after the typical recovery period of COVID-19. Despite the fact that this syndrome is not fully understood, it is urgent to develop strategies for diagnosing/managing long-COVID due to the immense potential for future disease burden. New diagnostic/therapeutic tools should provide health personnel with the ability to manage the consequences of long-COVID and preserve/improve patient quality of life. It has been shown that cardiovascular rehabilitation programs (CRPs) stimulate the parasympathetic nervous system, improve cardiorespiratory fitness (CRF), and reduce cardiovascular risk factors, hospitalization rates, and cognitive impairment in patients suffering from cardiovascular diseases. Given their efficacy in improving patient outcomes, CRPs may have salutary potential for the treatment of cardiovascular sequelae of long-COVID. Indeed, there are several public and private initiatives testing the potential of CRPs in treating fatigue and dysautonomia in long-COVID subjects. The application of these established rehabilitation techniques to COVID-19 cardiovascular syndrome represents a promising approach to improving functional capacity and quality of life. In this brief review, we will focus on the long-lasting cardiovascular and autonomic sequelae occurring after COVID-19 infection, as well as exploring the potential of classic and novel CRPs for managing COVID-19 cardiovascular syndrome. Finally, we expect this review will encourage health care professionals and private/public health organizations to evaluate/implement non-invasive techniques for the management of COVID-19 cardiovascular sequalae.
  • No Thumbnail Available
    Item
    Discovery of a Potent Dual Inhibitor of Acetylcholinesterase and Butyrylcholinesterase with Antioxidant Activity that Alleviates Alzheimer-like Pathology in Old APP/PS1 Mice
    (2021) Viayna, Elisabet; Coquelle, Nicolas; Cieslikiewicz-Bouet, Monika; Cisternas, Pedro; Oliva, Carolina A.; Sanchez-Lopez, Elena; Ettcheto, Miren; Bartolini, Manuela; De Simone, Angela; Ricchini, Mattia; Rendina, Marisa; Pons, Megane; Firuzi, Omidreza; Perez, Belen; Saso, Luciano; Andrisano, Vincenza; Nachon, Florian; Brazzolotto, Xavier; Luisa Garcia, Maria; Camins, Antoni; Silman, Israel; Jean, Ludovic; Inestrosa, Nibaldo C.; Colletier, Jacques-Philippe; Renard, Pierre-Yves; Munoz-Torrero, Diego
    The combination of the scaffolds of the cholinesterase inhibitor huprine Y and the antioxidant capsaicin results in compounds with nanomolar potencies toward human acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) that retain or improve the antioxidant properties of capsaicin. Crystal structures of their complexes with AChE and BChE revealed the molecular basis for their high potency. Brain penetration was confirmed by biodistribution studies in CS7BL6 mice, with one compound (Si) displaying better brain/plasma ratio than donepezil. Chronic treatment of 10 month-old APP/PS1 mice with 5i (2 mg/kg, i.p., 3 times per week, 4 weeks) rescued learning and memory impairments, as measured by three different behavioral tests, delayed the Alzheimer-like pathology progression, as suggested by a significantly reduced A beta 42/A beta 40 ratio in the hippocampus, improved basal synaptic efficacy, and significantly reduced hippocampal oxidative stress and neuroinflammation. Compound Si emerges as an interesting anti-Alzheimer lead with beneficial effects on cognitive symptoms and on some underlying disease mechanisms.
  • No Thumbnail Available
    Item
    Evidence of Synaptic and Neurochemical Remodeling in the Retina of Aging Degus
    (2020) Chang, Lily Y-L; Ardiles, Alvaro O.; Tapia-Rojas, Cheril; Araya, Joaquin; Inestrosa, Nibaldo C.; Palacios, Adrian G.; Acosta, Monica L.
    Accumulation of amyloid-beta (A beta) peptides is regarded as the hallmark of neurodegenerative alterations in the brain of Alzheimer's disease (AD) patients. In the eye, accumulation of A beta peptides has also been suggested to be a trigger of retinal neurodegenerative mechanisms. Some pathological aspects associated with A beta levels in the brain are synaptic dysfunction, neurochemical remodeling and glial activation, but these changes have not been established in the retina of animals with A beta accumulation. We have employed the Octodon degus in which A beta peptides accumulated in the brain and retina as a function of age. This current study investigated microglial morphology, expression of PSD95, synaptophysin, Iba-1 and choline acetyltransferase (ChAT) in the retina of juvenile, young and adult degus using immunolabeling methods. Neurotransmitters glutamate and gamma-aminobutyric acid (GABA) were detected using immunogold labeling and glutamate receptor subunits were quantified using Western blotting. There was an age-related increase in presynaptic and a decrease in post-synaptic retinal proteins in the retinal plexiform layers. Immunolabeling showed changes in microglial morphology characteristic of intermediate stages of activation around the optic nerve head (ONH) and decreasing activation toward the peripheral retina. Neurotransmitter expression pattern changed at juvenile ages but was similar in adults. Collectively, the results suggest that microglial activation, synaptic remodeling and neurotransmitter changes may be consequent to, or parallel to A beta peptide and phosphorylated tau accumulation in the retina.
  • No Thumbnail Available
    Item
    "Live together, die alone": The effect of re-socialization on behavioural performance and social-affective brain-related proteins after a long-term chronic social isolation stress
    (2021) Rivera, Daniela S.; Lindsay, Carolina B.; Oliva, Carolina A.; Bozinovic, Francisco; Inestrosa, Nibaldo C.
    Loneliness affects group-living mammals triggering a cascade of stress-dependent physiological disorders. Indeed, social isolation stress is a major risk factor for several neuropsychiatric disorders including anxiety and depression. Furthermore, social isolation has a negative impact on health and fitness. However, the neurobiological consequences of long-term chronic social isolation stress (LTCSIS) manifested during the adulthood of affected individuals are not fully understood. Our study assessed the impact of LTCSIS and social buffering (re-socialization) on the behavioural performance and social-affective brain-related proteins in diurnal, social, and long-lived Octodon degus (degus). Thereby, anxiety-like and social behaviour, and social recognition memory were assessed in male and female animals subjected to a variety of stress-inducing treatments applied from postnatal and post-weaning until their adulthood. Additionally, we evaluated the relationship among LTCSIS, Oxytocin levels (OXT), and OXT-Ca2+-signalling proteins in the hypothalamus, the hippocampus, and the prefrontal cortex. Our findings suggest that LTCSIS induces anxiety like-behaviour and impairs social novelty preference whereas sociability is unaffected. On the other hand, re-socialization can revert both isolation-induced anxiety and social memory impairment. However, OXT and its signalling remained reduced in the abovementioned brain areas, suggesting that the observed changes in OXT-Ca2+ pathway proteins were permanent in male and female degus. Based on these findings, we conclude degus experience social stress differently, suggesting the existence of sex-related mechanisms to cope with specific adaptive challenges.
  • No Thumbnail Available
    Item
    Long-term social isolation stress exacerbates sex-specific neurodegeneration markers in a natural model of Alzheimer's disease
    (2023) Oliva, Carolina A.; Lira, Matias; Jara, Claudia; Catenaccio, Alejandra; Mariqueo, Trinidad A.; Lindsay, Carolina B.; Bozinovic, Francisco; Cavieres, Grisel; Inestrosa, Nibaldo C.; Tapia-Rojas, Cheril; Rivera, Daniela S.
    Social interactions have a significant impact on health in humans and animal models. Social isolation initiates a cascade of stress-related physiological disorders and stands as a significant risk factor for a wide spectrum of morbidity and mortality. Indeed, social isolation stress (SIS) is indicative of cognitive decline and risk to neurodegenerative conditions, including Alzheimer's disease (AD). This study aimed to evaluate the impact of chronic, long-term SIS on the propensity to develop hallmarks of AD in young degus (Octodon degus), a long-lived animal model that mimics sporadic AD naturally. We examined inflammatory factors, bioenergetic status, reactive oxygen species (ROS), oxidative stress, antioxidants, abnormal proteins, tau protein, and amyloid-beta (A beta) levels in the hippocampus of female and male degus that were socially isolated from post-natal and post-weaning until adulthood. Additionally, we explored the effect of re-socialization following chronic isolation on these protein profiles. Our results showed that SIS promotes a pro-inflammatory scenario more severe in males, a response that was partially mitigated by a period of re-socialization. In addition, ATP levels, ROS, and markers of oxidative stress are severely affected in female degus, where a period of re-socialization fails to restore them as it does in males. In females, these effects might be linked to antioxidant enzymes like catalase, which experience a decline across all SIS treatments without recovery during re-socialization. Although in males, a previous enzyme in antioxidant pathway diminishes in all treatments, catalase rebounds during re-socialization. Notably, males have less mature neurons after chronic isolation, whereas phosphorylated tau and all detectable forms of A beta increased in both sexes, persisting even post re-socialization. Collectively, these findings suggest that long-term SIS may render males more susceptible to inflammatory states, while females are predisposed to oxidative states. In both scenarios, the accumulation of tau and A beta proteins increase the individual susceptibility to early-onset neurodegenerative conditions such as AD.
  • Thumbnail Image
    Item
    Methionine sulfoxide reductase A expression is regulated by the DAF-16/FOXO pathway in Caenorhabditis elegans
    (WILEY, 2009) Minniti, Alicia N.; Cataldo, Romina; Trigo, Carla; Vasquez, Luis; Mujica, Patricio; Leighton, Federico; Inestrosa, Nibaldo C.; Aldunate, Rebeca
    P>The methionine sulfoxide reductase system has been implicated in aging and protection against oxidative stress. This conserved system reverses the oxidation of methionine residues within proteins. We analyzed one of the components of this system, the methionine sulfoxide reductase A gene, in Caenorhabditis elegans. We found that the msra-1 gene is expressed in most tissues, particularly in the intestine and the nervous system. Worms carrying a deletion of the msra-1 gene are more sensitive to oxidative stress, show chemotaxis and locomotory defects, and a 30% decrease in median survival. We established that msra-1 expression decreases during aging and is regulated by the DAF-16/FOXO3a transcription factor. The absence of this enzyme decreases median survival and affects oxidative stress resistance of long lived daf-2 worms. A similar effect of MSRA-1 absence in wild-type and daf-2 (where most antioxidant enzymes are activated) backgrounds, suggests that the lack of this member of the methionine repair system cannot be compensated by the general antioxidant response. Moreover, FOXO3a directly activates the human MsrA promoter in a cell culture system, implying that this could be a conserved mechanism of MsrA regulation. Our results suggest that repair of oxidative damage in proteins influences the rate at which tissues age. This repair mechanism, rather than the general decreased of radical oxygen species levels, could be one of the main determinants of organisms' lifespan.
  • No Thumbnail Available
    Item
    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.
  • No Thumbnail Available
    Item
    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.
  • No Thumbnail Available
    Item
    Wnt-5a induces the conversion of silent to functional synapses in the hippocampus
    (2022) Alvarez-Ferradas, Carla; Wellmann, Mario; Morales, Koyam; Fuenzalida, Marco; Cerpa, Waldo; Inestrosa, Nibaldo C.; Bonansco, Christian
    Synapse unsilencing is an essential mechanism for experience-dependent plasticity. Here, we showed that the application of the ligand Wnt-5a converts glutamatergic silent synapses into functional ones by increasing both alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and N-methyl-D-aspartate (NMDA) currents (I-AMPA and I-NMDA, respectively). These effects were mimicked by the hexapeptide Foxy-5 and inhibited by secreted frizzled-related protein sFRP-2. I-NMDA potentiation was produced by increased synaptic potency, followed by an increase in the probability of release (Pr), even in the presence of 7-nitro-2,3-dioxo-1,4-dihydroquinoxaline-6-carbonitrile (CNQX). At a longer time of Wnt-5a exposure, the Pr increments were higher in I-NMDA than in I-AMPA. In the presence of NMDAR inhibitors, Wnt-5a-induced conversion was fully inhibited in 69.0% of silent synapses, whereas in the remaining synapses were converted into functional one. Our study findings showed that the Wnt-5a-activated pathway triggers AMPAR insertion into mammalian glutamatergic synapses, unsilencing non-functional synapses and promoting the formation of nascent synapses during the early postnatal development of the brain circuits.
  • No Thumbnail Available
    Item
    Wnt-5a Signaling Mediates Metaplasticity at Hippocampal CA3-CA1 Synapses in Mice
    (2024) Parodi, Jorge; Mira, Rodrigo G.; Fuenzalida, Marco; Cerpa, Waldo; Serrano, Felipe G.; Tapia-Rojas, Cheril; Martinez-Torres, Ataulfo; Inestrosa, Nibaldo C.
    Wnt signaling plays a role in synaptic plasticity, but the specific cellular events and molecular components involved in Wnt signaling-mediated synaptic plasticity are not well defined. Here, we report a change in the threshold required to induce synaptic plasticity that facilitates the induction of long-term potentiation (LTP) and inhibits the induction of long-term depression (LTD) during brief exposure to the noncanonical ligand Wnt-5a. Both effects are related to the metaplastic switch of hippocampal CA3-CA1 synaptic transmission, a complex mechanism underlying the regulation of the threshold required to induce synaptic plasticity and of synaptic efficacy. We observed an early increase in the amplitude of field excitatory postsynaptic potentials (fEPSPs) that persisted over time, including after washout. The first phase involves an increase in the fEPSP amplitude that is required to trigger a spontaneous second phase that depends on Jun N-terminal kinase (JNK) and N-methyl D-aspartate receptor (NMDAR) activity. These changes are prevented by treatment with secreted frizzled-related protein 2 (sFRP-2), an endogenous antagonist of Wnt ligands. Here, we demonstrate the contribution of Wnt-5a signaling to a process associated with metaplasticity at CA3-CA1 synapses that favors LTP over LTD.