Browsing by Author "Zolezzi, Juan M."

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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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    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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    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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    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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    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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    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.