Browsing by Author "Cisternas, Pedro"

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    Activation of Wnt Signaling in Cortical Neurons Enhances Glucose Utilization through Glycolysis
    (2016) Cisternas, Pedro; Salazar, Paulina; Silva Alvarez, Carmen; Barros, L. Felipe; Inestrosa Cantín, Nibaldo
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    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.
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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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    Age- and Sex-Associated Glucose Metabolism Decline in a Mouse Model of Alzheimer's Disease
    (2022) Gherardelli, Camila; Cisternas, Pedro; Vera-Salazar, Roberto F.; Mendez-Orellana, Carolina; Inestrosa, Nibaldo C.
    Background: Alzheimer's disease (AD) is characterized by a high etiological and clinical heterogeneity, which has obscured the diagnostic and treatment efficacy, as well as limited the development of potential drugs. Sex differences are among the risk factors that contribute to the variability of disease manifestation. Unlike men, women are at greater risk of developing AD and suffer from higher cognitive deterioration, together with important changes in pathological features. Alterations in glucose metabolism are emerging as a key player in the pathogenesis of AD, which appear even decades before the presence of clinical symptoms.
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    Andrographolide Reduces Neuroinflammation and Oxidative Stress in Aged Octodon degus
    (SPRINGER, 2020) Lindsay, Carolina B.; Zolezzi, Juan M.; Rivera, Daniela S.; Cisternas, Pedro; Bozinovic, Francisco; Inestrosa, Nibaldo C.
    Alzheimer's disease (AD) is a devastating neurodegenerative disorder in which superior brain functions, such as memory and cognition, are impaired. Currently, no effective treatment is available for AD. Although andrographolide (ANDRO), a compound extracted from the herb Andrographis paniculata, has shown interesting effects in models of several diseases, including AD, its effects on other molecular changes observed in AD, such as neuroinflammation and oxidative stress, have not yet been studied. To evaluate the impact of ANDRO-based intervention on the levels of amyloid-beta (A beta) and neuroinflammatory and oxidative stress markers in the brains of aged Octodon degus, a Chilean rodent, fifty-six-month-old O. degus were treated intraperitoneally with 2 or 4 mg/kg ANDRO. Vehicle-injected and 12-month-old O. degus were used as positive controls. Then, the protein levels of selected markers were assessed via immunohistochemistry and immunoblotting. ANDRO significantly reduced the total A beta burden as well as astrogliosis and interleukin-6 levels. Moreover, ANDRO significantly reduced the levels of 4-hydroxynonenal and N-tyrosine adducts, suggesting a relevant reduction in oxidative stress within aged O. degus brain. Considering that O. degus has been proposed as a potential "natural" model for sporadic AD due to the development of neuropathological markers that resemble this pathology, our results suggest that ANDRO should be further studied to establish its potential as a therapeutic drug for AD.
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    Andrographolide restores glucose uptake in rat hippocampal neurons
    (2020) Gherardelli Brooks, Camila; Cisternas, Pedro; Gutiérrez, Joel; Martínez, Milka; Inestrosa Cantín, Nibaldo
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    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.
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    Disruption of Glucose Metabolism in Aged Octodon degus: A Sporadic Model of Alzheimer's Disease
    (2021) Cisternas, Pedro; Gherardelli, Camila; Salazar, Paulina; Inestrosa, Nibaldo C.
    Alzheimer's disease is a progressive neurodegenerative disorder and the most common cause of dementia. Although transgenic Alzheimer's disease (AD) animal models have greatly contributed to our understanding of the disease, therapies tested in these animals have resulted in a high rate of failure in preclinical trials for AD. A promising model is Octodon degus (degu), a Chilean rodent that spontaneously develops AD-like neuropathology. Previous studies have reported that, during aging, degus exhibit a progressive decline in cognitive function, reduced neuroinflammation, and concomitant increases in the number and size of amyloid beta (A beta) plaques in several brain regions. Importantly, in humans and several AD models, a correlation has been shown between brain dysfunction and neuronal glucose utilization impairment, a critical aspect considering the high-energy demand of the brain. However, whether degus develop alterations in glucose metabolism remains unknown. In the present work, we measured several markers of glucose metabolism, namely, glucose uptake, ATP production, and glycolysis and pentose phosphate pathway (PPP) flux, in hippocampal slices from degus of different ages. We found a significant decrease in hippocampal glucose metabolism in aged degus, caused mainly by a drop in glucose uptake, which in turn, reduced ATP synthesis. Moreover, we observed a negative correlation between age and PPP flux. Together, our data further support the use of degus as a model for studying the neuropathology involved in sporadic AD-like pathology and as a potentially valuable tool in the search for effective treatments against the disease.
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    Dynamic expression of the sodium-vitamin C co-transporters, SVCT1 and SVCT2, during perinatal kidney development
    (2013) Nualart, Francisco; Castro, Tamara; Low, Marcela; Henríquez, Juan Pablo; Oyarce, Karina; Cisternas, Pedro; García, Andra; Yañez, Alejandro J.; Bertinat, Romina; Montecinos Acuña, Viviana; García Robles, María Angeles
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    FAM19A1, a brain-enriched and metabolically responsive neurokine, regulates food intake patterns and mouse behaviors
    (2019) Lei, Xia; Liu, Lili; Terrillion, Chantelle E.; Karuppagounder, Senthilkumar S.; Cisternas, Pedro; Lay, Mark; Martinelli, David C.; Aja, Susan; Dong, Xinzhong; Pletnikov, Mikhail, V; Wong, G. William
    Cytokines and chemokines play diverse roles in different organ systems. Family with sequence similarity 19, member A1-5 (FAM19A1-A5; also known as TAFA1-5) is a group of conserved chemokine-like proteins enriched in the CNS of mice and humans. Their functions are only beginning to emerge. Here, we show that the expression of Fam19a1-a5 in different mouse brain regions are induced or suppressed by unfed and refed states. The striking nutritional regulation of Fam19a family members in the brain suggests a potential central role in regulating metabolism. Using a knockout (KO) mouse model, we show that loss of FAM19A1 results in sexually dimorphic phenotypes. In male mice, FAM19A1 deficiency alters food intake patterns during the light and dark cycle. Fam19a1 KO mice are hyperactive, and locomotor hyperactivity is more pronounced in female KO mice. Behavior tests indicate that Fam19a1 KO female mice have reduced anxiety and sensitivity to pain. Spatial learning and exploration, however, is preserved in Fam19a1 KO mice. Altered behaviors are associated with elevated norepinephrine and dopamine turnover in the striatum. Our results establish an in vivo function of FAM19A1 and highlight central roles for this family of neurokines in modulating animal physiology and behavior.
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    Fructose consumption reduces hippocampal synaptic plasticity underlying cognitive performance
    (2015) Cisternas, Pedro; Salazar, Paulina; Serrano, Felipe G.; Montecinos Oliva, Carla; Arredondo, Sebastián B.; Varela Nallar, Lorena Patricia; Barja Y., Salesa; Vio Lagos, Carlos P.; Gomez Pinilla, Fernando; Inestrosa Cantín, Nibaldo
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    Inflammation context in Alzheimer’s disease, a relationship intricate to define
    (2022) Novoa Fernández, Catalina; Salazar Torres, Paulina Isabel; Cisternas, Pedro; Gherardelli Brooks, Camila; Vera Salazar, Roberto; Zolezzi, Juan M.; Inestrosa Cantín, Nibaldo
    Alzheimer’s disease (AD), the most common form of dementia, is characterized by the accumulation of amyloid β (Aβ) and hyperphosphorylated tau protein aggregates. Importantly, Aβ and tau species are able to activate astrocytes and microglia, which release several proinflammatory cytokines, such as tumor necrosis factor α (TNF-α) and interleukin 1β (IL-1β), together with reactive oxygen (ROS) and nitrogen species (RNS), triggering neuroinflammation. However, this inflammatory response has a dual function: it can play a protective role by increasing Aβ degradation and clearance, but it can also contribute to Aβ and tau overproduction and induce neurodegeneration and synaptic loss. Due to the significant role of inflammation in the pathogenesis of AD, several inflammatory mediators have been proposed as AD markers, such as TNF-α, IL-1β, Iba-1, GFAP, NF-κB, TLR2, and MHCII. Importantly, the use of anti-inflammatory drugs such as NSAIDs has emerged as a potential treatment against AD. Moreover, diseases related to systemic or local inflammation, including infections, cerebrovascular accidents, and obesity, have been proposed as risk factors for the development of AD. In the following review, we focus on key inflammatory processes associated with AD pathogenesis.
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    Lithium Enhances Hippocampal Glucose Metabolism in an In Vitro Mice Model of Alzheimer's Disease
    (2022) Gherardelli, Camila; Cisternas, Pedro; Inestrosa, Nibaldo C.
    Impaired cerebral glucose metabolism is an early event that contributes to the pathogenesis of Alzheimer's disease (AD). Importantly, restoring glucose availability by pharmacological agents or genetic manipulation has been shown to protect against A beta toxicity, ameliorate AD pathology, and increase lifespan. Lithium, a therapeutic agent widely used as a treatment for mood disorders, has been shown to attenuate AD pathology and promote glucose metabolism in skeletal muscle. However, despite its widespread use in neuropsychiatric disorders, lithium's effects on the brain have been poorly characterized. Here we evaluated the effect of lithium on glucose metabolism in hippocampal neurons from wild-type (WT) and APPSwe/PS1 Delta E9 (APP/PS1) mice. Our results showed that lithium significantly stimulates glucose uptake and replenishes ATP levels by preferential oxidation of glucose through glycolysis in neurons from WT mice. This increase was also accompanied by a strong increase in glucose transporter 3 (Glut3), the major carrier responsible for glucose uptake in neurons. Similarly, using hippocampal slices from APP-PS1 mice, we demonstrate that lithium increases glucose uptake, glycolytic rate, and the ATP:ADP ratio in a process that also involves the activation of AMPK. Together, our findings indicate that lithium stimulates glucose metabolism and can act as a potential therapeutic agent in AD.
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    New Insights into the Spontaneous Human Alzheimer's Disease-Like Model Octodon degus : Unraveling Amyloid-beta Peptide Aggregation and Age-Related Amyloid Pathology
    (2018) Cisternas, Pedro; Zolezzi, Juan M.; Lindsay, Carolina; Rivera, Daniela S.; Martinez, Alexis; Bozinovic Kuscevic, Francisco; Inestrosa Cantín, Nibaldo
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    Rhein-Huprine Derivatives Reduce Cognitive Impairment, Synaptic Failure and Amyloid Pathology in A beta PPswe/PS-1 Mice of Different Ages
    (2016) Serrano, Felipe G.; Tapia Rojas, Cheril Cecilia; Carvajal Cachaña, Francisco Javier; Cisternas, Pedro; Viayna, Elisabet; Sola, Irene; Muñoz Torrero, Diego; Inestrosa Cantín, Nibaldo
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    Role of Wnt Signaling in Central Nervous System Injury
    (2016) Lambert, Catherine; Cisternas, Pedro; Inestrosa Cantín, Nibaldo
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    The increased potassium intake improves cognitive performance and attenuates histopathological markers in a model of Alzheimer's disease
    (2015) Cisternas, Pedro; Lindsay, Carolina B.; Salazar, Paulina; Silva Álvarez, Carmen; Retamales, Rocio M.; Serrano, Felipe G.; Vio Lagos, Carlos P.; Inestrosa Cantín, Nibaldo
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    Wnt-induced activation of glucose metabolism mediates the in vivo neuroprotective roles of Wnt signaling in Alzheimer disease
    (WILEY, 2019) Cisternas, Pedro; Zolezzi, Juan M.; Martinez, Milka; Torres, Viviana I.; Wong, Guang William; Inestrosa, Nibaldo C.
    Dysregulated Wnt signaling is linked to major neurodegenerative diseases, including Alzheimer disease (AD). In mouse models of AD, activation of the canonical Wnt signaling pathway improves learning/memory, but the mechanism for this remains unclear. The decline in brain function in AD patients correlates with reduced glucose utilization by neurons. Here, we test whether improvements in glucose metabolism mediate the neuroprotective effects of Wnt in AD mouse model. APPswe/PS1dE9 transgenic mice were used to model AD, Andrographolide or Lithium was used to activate Wnt signaling, and cytochalasin B was used to block glucose uptake. Cognitive function was assessed by novel object recognition and memory flexibility tests. Glucose uptake and the glycolytic rate were determined using radiotracer glucose. The activities of key enzymes of glycolysis such as hexokinase and phosphofructokinase, Adenosine triphosphate (ATP)/Adenosine diphosphate (ADP) levels and the pentose phosphate pathway and activity of glucose-6 phosphate dehydrogenase were measured. Wnt activators significantly improved brain glucose utilization and cognitive performance in transgenic mice. Wnt signaling enhanced glucose metabolism by increasing the expression and/or activity of hexokinase, phosphofructokinase and AMP-activated protein kinase. Inhibiting glucose uptake partially abolished the beneficial effects of Wnt signaling on learning/memory. Wnt activation also enhanced glucose metabolism in cortical and hippocampal neurons, as well as brain slices derived from APPswe/PS1E9 transgenic mice. Combined, these data provide evidence that the neuroprotective effects of Wnt signaling in AD mouse models result, at least in part, from Wnt-mediated improvements in neuronal glucose metabolism.