Browsing by Author "Gherardelli, Camila"

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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- 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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    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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    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.