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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. Dysregulated Wnt signaling is linked to major neurodegenerative diseases, including Alzheimer disease (AD). 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. Wnt activators significantly improved brain glucose utilization and cognitive performance in transgenic mice. The neuroprotective effects of Wnt signaling in AD mouse models result, at least in part, from Wnt‐mediated improvements in neuronal glucose metabolism. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is the most common cause of dementia worldwide. Despite advances in our understanding of the molecular milieu driving AD pathophysiology, no effective therapy is currently available. Moreover, various clinical trials have continued to fail, suggesting that our approach to AD must be revised. Accordingly, the development and validation of new models are highly desirable. Over the last decade, we have been working with Octodon degus (degu), a Chilean rodent, which spontaneously develops AD-like neuropathology, including increased amyloid-β (Aβ) aggregates, tau hyperphosphorylation, and postsynaptic dysfunction. However, for proper validation of degu as an AD model, the aggregation properties of its Aβ peptide must be analyzed. Thus, in this study, we examined the capacity of the degu Aβ peptide to aggregate in vitro. Then, we analyzed the age-dependent variation in soluble Aβ levels in the hippocampus and cortex of third- to fifth-generation captive-born degu. We also assessed the appearance and spatial distribution of amyloid plaques in O. degus and compared them with the plaques in two AD transgenic mouse models. In agreement with our previous studies, degu Aβ was able to aggregate, forming fibrillar species in vitro. Furthermore, amyloid plaques appeared in the anterior brain structures of O. degus at approximately 32 months of age and in the whole brain at 56 months, along with concomitant increases in Aβ levels and the Aβ42/Aβ40 ratio, indicating that O. degus spontaneously develops AD-like pathology earlier than other spontaneous models. Based on these results, we can confirm that O. degus constitutes a valuable model to improve AD research. [ABSTRACT FROM AUTHOR]

ABSTRACT Over 25 years have passed since peroxisome proliferators-activated receptors ( PPARs), were first described. Like other members of the nuclear receptors superfamily, PPARs have been defined as critical sensors and master regulators of cellular metabolism. Recognized as ligand-activated transcription factors, they are involved in lipid, glucose and amino acid metabolism, taking part in different cellular processes, including cellular differentiation and apoptosis, inflammatory modulation and attenuation of acute and chronic neurological damage in vivo and in vitro. Interestingly, PPAR activation can simultaneously reprogram the immune response, stimulate metabolic and mitochondrial functions, promote axonal growth, induce progenitor cells to differentiate into myelinating oligodendrocytes, and improve brain clearance of toxic molecules such as β-amyloid peptide. Although the molecular mechanisms and cross-talk with different molecular pathways are still the focus of intense research, PPARs are considered potential therapeutic targets for several neuropathological conditions, including degenerative disorders such as Alzheimer's, Parkinson's and Huntington's disease. This review considers recent advances regarding PPARs, as well as new PPAR agonists. We focus on the mechanisms behind the neuroprotective effects exerted by PPARs and summarise the roles of PPARs in different pathologies of the central nervous system, especially those associated with degenerative and inflammatory mechanisms. [ABSTRACT FROM AUTHOR]

In previous studies, we have demonstrated the beneficial effects of classic PPARγ agonists on neuroprotection against Aβ oligomer neurotoxicity in a double transgenic mouse model of Alzheimer' disease (AD). INT-131, a novel, non-thiazolidinedione compound that belongs to a new family of drugs, selective PPARγ modulators (SPPARMs), has provided an emerging opportunity for the treatment of type 2 diabetes mellitus and metabolic syndrome. However, its role in the central nervous system has not been studied. The aim of this study was to evaluate the putative neuroprotective role of INT131 in hippocampal neurons. We found that INT131 increased dendritic branching, promoted neuronal survival against Aβ amyloid, increased expression of PGC1-1α and modulated neuronal mitochondrial dynamics. Our results suggest that INT131, a drug that has been shown to be safe and effective in metabolic disorders, may constitute a new therapeutic alternative for AD. [ABSTRACT FROM AUTHOR]

Alzheimer's Disease (AD) is a complex neurodegenerative disorder often associated with aging and characterized by several critical molecular changes that take place in the brain. Among the molecular hallmarks of AD, increased levels of amyloid β-peptide (Aβ) and the subsequent Aβ-derived damage are the most well-studied factors; however, despite the large amounts of effort and resources devoted to the study of AD and AD pathophysiology, the scientific community still awaits therapeutic alternatives capable of ensuring a better outcome for AD patients. In 2012, Cramer et al. (Science 335:1503-1506 ) astonished the scientific community by rescuing behavioral and cognitive impairments in AD mouse models via oral administration of bexarotene, a drug used to treat some types of skin cancer. Moreover, these authors demonstrated that bexarotene, a retinoid X receptor (RXR) agonist, exerts major effects on Aβ levels, mainly through increased apolipoprotein E (ApoE) expression. Apart from the valid questions addressed in Cramer's work, only a few attempts have been made to explain the effects of bexarotene. Most of these explanations have been solely based on the ability of bexarotene to reduce Aβ levels and not on the mechanisms that lead to such a reduction. Although it is well known that an imbalance in the Aβ production/excretion rate is the basis of increased Aβ levels in AD, no further explanations have been proposed to address the potential involvement of the blood-brain barrier (BBB), a critical Aβ-clearance structure, in the bexarotene-mediated effects. Moreover, no attempt has been made to explain how the different effects observed after bexarotene administration are connected to each other. Based on current information and on our own experience with nuclear receptors (NR), we offer new perspectives on the mechanisms of bexarotene action, which should help to improve our knowledge of NRs. [ABSTRACT FROM AUTHOR]

St. John's wort has been the subject of studies focused on its therapeutic properties against several diseases, including Alzheimer's disease (AD). Amyloid β-peptide (Aβ), a critical peptide in AD, has been linked to the mitochondrial dysfunction often observed in this disease. Despite many efforts to prevent Aβ levels from increasing in AD, less has been done regarding the mitochondrial component. Therefore, we studied the effects of tetrahydrohyperforin (THH) on mitochondrial dysfunction of hippocampal neurons, challenged with Aβ oligomers (Aβo) and Aβo-AChE complexes. We show that THH prevents mitochondrial calcium overload and induces the modulation of fusion-fission events, arresting mitochondrial dysfunction. Moreover, our results suggest that the modulation of mitochondrial dynamics probably occurs through a peroxisome proliferator-activated receptor γ co-activator 1α-mediated mechanism, inducing mitochondrial fusion-fission protein expression. Our results offer further explanation for the effects observed for THH and the beneficial effects of this ethno-botanical drug in AD. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a progressive deterioration of cognitive abilities, amyloid-β peptide (Aβ) accumulation, neurofibrillary tangle deposition, synaptic alterations, and oxidative injury. In AD patients, acetylcholinesterase (AChE) activity is low in most regions of the brain, but increased within and around amyloid plaques, where it accelerates the Aβ assembly into oligomers and fibrils, increasing its neurotoxicity. Tetrahydrohyperforin (THH), a semi-synthetic derivative of hyperforin, reduces tau phosphorylation and Aβ accumulation in AD mouse models. In the present study, we examined the effects of THH on Aβ-AChE complexes, α7-nicotinic acetylcholine receptors (α7-nAChR), 4-hydroxynonenal (4-HNE) adducts, caspase-3 activation, and spatial memory in young AβPPSwe/PSEN1ΔE9 (AβPP/PS1) transgenic mice, in order to evaluate its potential preventive effects on the development of the disease. We report here that treatment with THH prevents the association of AChE to different types of amyloid plaques; partially restores the brain distribution of AChE molecular forms; increases α7-nAChR levels in the hippocampus of treated mice; decreases the amount of these receptors in amyloid plaques; and reduces the oxidative damage, evidenced by 4-HNE adduct formation and caspase-3 activation on AβPP/PS1 mice brain; demonstrating the neuroprotective properties of THH. Finally, we found that the acute treatment of hippocampal neurons with THH, in the presence of Aβ-AChE complexes, prevents 4-HNE adduct formation and caspase-3 activation. Our data support a therapeutic potential of THH for the treatment of AD. [ABSTRACT FROM AUTHOR]

Recent studies showed that the activation of the retinoid X receptor, which dimerizes with peroxisome proliferator-activated receptors (PPARs), leads to an enhanced clearance of Aβ from the brain of transgenic mice model of Alzheimer’s disease (AD), because an increased expression of apolipoprotein E and it main transporters. However, the effects observed must involve additional underlying mechanisms that have not been yet explored. Several studies conducted in our laboratory suggest that part of the effects observed for the PPARs agonist might involves mitochondrial function and, particularly, mitochondrial dynamics. In the present study we assessed the effects of oxidative stress challenge on mitochondrial morphology and mitochondrial dynamics-related proteins in hippocampal neurons. Using immunofluorescence, we evaluated the PPARγ co-activator 1α (PGC-1α), dynamin related protein 1 (DRP1), mitochondrial fission protein 1 (FIS1), and mitochondrial length, in order to determine if PPARs agonist pre-treatment is able to protect mitochondrial population from hippocampal neurons through modulation of the mitochondrial fusion-fission events. Our results suggest that both a PPARγ agonist (ciglitazone) and a PPARα agonist (WY 14.643) are able to protect neurons by modulating mitochondrial fusion and fission, leading to a better response of neurons to oxidative stress, suggesting that a PPAR based therapy could acts simultaneously in different cellular components. Additionally, our results suggest that PGC-1α and mitochondrial dynamics should be further studied in future therapy research oriented to ameliorate neurodegenerative disorders, such as AD. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a progressive deterioration of cognitive abilities, amyloid-β peptide (Aβ) accumulation, neurofibrillary tangle deposition, synaptic alterations, and oxidative injury. In AD patients, acetylcholinesterase (AChE) activity is low in most regions of the brain, but increased within and around amyloid plaques, where it accelerates the Aβ assembly into oligomers and fibrils, increasing its neurotoxicity. Tetrahydrohyperforin (THH), a semi-synthetic derivative of hyperforin, reduces tau phosphorylation and Aβ accumulation in AD mouse models. In the present study, we examined the effects of THH on Aβ-AChE complexes, α7-nicotinic acetylcholine receptors (α7-nAChR), 4-hydroxynonenal (4-HNE) adducts, caspase-3 activation, and spatial memory in young AβPPSwe/PSEN1ΔE9 (AβPP/PS1) transgenic mice, in order to evaluate its potential preventive effects on the development of the disease. We report here that treatment with THH prevents the association of AChE to different types of amyloid plaques; partially restores the brain distribution of AChE molecular forms; increases α7-nAChR levels in the hippocampus of treated mice; decreases the amount of these receptors in amyloid plaques; and reduces the oxidative damage, evidenced by 4-HNE adduct formation and caspase-3 activation on AβPP/PS1 mice brain; demonstrating the neuroprotective properties of THH. Finally, we found that the acute treatment of hippocampal neurons with THH, in the presence of Aβ-AChE complexes, prevents 4-HNE adduct formation and caspase-3 activation. Our data support a therapeutic potential of THH for the treatment of AD. [ABSTRACT FROM AUTHOR]

A method is presented that allows finding the market clearance prices within a hydrothermal power exchange market that incorporates network constraints. An analysis is made of the degree of market power exerted by the various agents. The Nash-Cournot equilibrium solution of the market is achieved using the Nikaido-Isoda function, which is derived from the profit maximization functions calculated by the generating companies. Both thermal, hydro generation, and network constraints are considered in the model, with coupling constraints of the hydro units also taken into account. The model is applied to the main Chilean interconnected power system, whose abundant hydro production and existing network bottlenecks make it a valuable suitable case for study. The results for pool-based and bilateral contract markets highlight the strength of the method and show the contribution of the transmission system and hydro constraints. [ABSTRACT FROM AUTHOR]

Proposes a cost assignment model for the expansion of electrical transmission systems based on the cooperation and interaction principles that are the foundation of the cooperative game theory. Characteristics to create coalitions, payment factors and general features of cooperative games; Advantages and disadvantages of the use of the Kernel theory in developing the cost assignment model; Application of the model to the classical Garvier six-bus problem.

Presents a study that examined a method to allocate charges among users of a transmission system, either in an existing network or an expanding one. Features of the method; Background on the deregulation of the power industry; Methods in identifying the impact of a generator on the flow of a transmission line.

The sub-Antarctic Magellan Ecoregion is a unique biogeographic area located at the southern tip of South America, which has exceptional marine flora and high endemism. Along the coastline, the ochrophytes Macrocystis pyrifera and Lessonia flavicans form vital underwater forests that serve as critical habitats, providing shelter, food and breeding grounds for a diverse marine organisms. These algal species are also important components used in the food industry and biomedicine, due to their high lipid, amino acid and fiber content. In this study, we investigated the intra-thallus variation of fatty acids among the different morphological structures (fronds, stipes and holdfast) of M. pyrifera and L. flavicans collected in Rinconada Bulnes during spring, 2021. The stipes of M. pyrifera (3.73 ± 1.73%) and the fronds of L. flavicans (3.35 ± 0.97%) both exhibited high lipid content. Saturated fatty acids were highest in the holdfast of M. pyrifera (37.82 ± 0.06%) followed by the fronds of L. flavicans (34.30 ± 0.10%). Notably, monounsaturated fatty acids showed higher levels en the holdfast of L. flavicans (46.45 ± 0.19%) followed by the stipes of M. pyrifera (43.04 ± 0.08%). The fronds of both M. pyrifera (32.38 ± 0.26%) and L. flavicans (28.89 ± 0.23%) showed high levels of polyunsaturated fatty acids. These findings provide valuable insight into the intra-thallus variation of fatty acids in different morphological structures of M. pyrifera and L. flavicans, highlighting their potential nutritional and biomedical importance as the most representative kelps in the Magellan region. [ABSTRACT FROM AUTHOR]

Discusses a study which compared methods to determine the use of power transmission lines. Criticisms on the study; Relevance of the subject in the discussions on transmission open access; Comments on the calculations of flow contributions.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a progressive deterioration of cognitive abilities, accumulation of the amyloid-β peptide (Aβ), increase of oxidative stress, and synaptic alterations. The scavenging of reactive oxygen species through their matrix enzyme catalase is one of the most recognized functions of peroxisomes. The induction of peroxisome proliferation is attained through different mechanisms by a set of structurally diverse molecules called peroxisome proliferators. In the present work, a double transgenic mouse model of AD that co-expresses a mutant human amyloid-β protein precursor (AβPPswe) and presenilin 1 without exon 9 (PS1dE9) was utilized in order to assess the effect of peroxisomal proliferation on Aβ neurotoxicity in vivo. Mice were tested for spatial memory and their brains analyzed by cytochemical, electrophysiological, and biochemical methods. We report here that peroxisomal proliferation significantly reduces (i) memory impairment, found in this model of AD; (ii) Aβ burden and plaque-associated acetylcholinesterase activity; (iii) neuroinflammation, measured by the extent of astrogliosis and microgliosis; and (iv) the decrease in postsynaptic proteins, while promoting synaptic plasticity in the form of long-term potentiation. We concluded that peroxisomal proliferation reduces various AD neuropathological markers and peroxisome proliferators may be considered as potential therapeutic agents against the disease. [ABSTRACT FROM AUTHOR]

Under a context of transmission open access, a methodology to define a common transmission trunk system using economic and technical criteria is proposed. A transmission trunk system is defined as a unique and common system constituted by electrical lines and substations that are economically efficient and necessary to allow the development of an electrical market and the supply of demand in the respective electrical system at a minimum cost and in an efficient manner. The principles of cooperation and interaction between agents that are the base for the cooperative games theory are used. Simple games and the Shapley value approach are used. The proposal responds to the need to identify a common main system, common to supply and demand agents, needed in system open access schemes in electricity markets. [ABSTRACT FROM AUTHOR]

This paper investigates the causal effect of COVID-19 quarantine measures on the electricity consumption of different types of regulated customers. In particular, the average energy consumption of a group of customers in Chile is examined, exploiting the weekly variations in the application of the stages of the Step by Step Plan as a natural experiment. Step by Step Plan was the Chile COVID containment strategy, which involved implementing partial lockdowns based on the COVID incidence in the municipalities, and adjusted on a weekly basis. An econometric model is specified, and estimated using the technique Difference-in-Difference-in-Difference (DDD) to quantify the causal impact of these measures. After applying the model, it is found that the quarantine measures have had a negative effect on the trend weekly consumption of customers located in municipalities where some of the phases of the Plan have been applied. This effect is significantly different depending on each stage of the plan analysis, and statistically significant. It is also observed that, on average, the savings for a representative customer in the sample range from $ 8 to $ 6. 15 for some municipalities, and the sample costs range from $ 0. 02 to $ 0. 26 for others, depending on the municipality analyzed. The results can be expressed in a total of 2.95 tons less CO 2 emitted on a monthly basis. This shows a great impact in terms of sustainability and planning of energy demand and supply. • Quarantines by Covid 19 affected energy consumption, like a "Natural Experiment". • Using Panel Data of 400 thousand observations with geographic, temporal and Daylight Saving Time controls. • Difference-in-Difference-in-Difference method to quantify causal impact of quarantines on electric consumption. • Applying quarantines generated Energetic Savings from 8 cents to 6.15 dollars depending on client type. • An Event Study was designed to check the estimation results. [ABSTRACT FROM AUTHOR]

Soluble amyloid-β (Aβ) oligomers have been recognized as early neurotoxic intermediates with a key role in the synaptic dysfunction observed in Alzheimer's disease (AD). Aβ oligomers block hippocampal long-term potentiation (LTP) and impair rodent spatial memory. Additionally, the presence of Aβ oligomers is associated with imbalanced intracellular calcium levels and apoptosis in neurons. In this context, we evaluated the effects of three diterpenes (ferruginol, jatrophone, and junicedric acid) that are found in medicinal plants and have several forms of biological activity. The intracellular calcium levels in hippocampal neurons increased in the presence of ferruginol, jatrophone, and junicedric acid, a result that was consistent with the observed increase in CA1 synaptic transmission in mouse hippocampal slices. Additionally, assays using Aβ peptide demonstrated that diterpenes, particularly ferruginol, restore LTP and reduce apoptosis. Recovery of the Aβ oligomer-induced loss of the synaptic proteins PSD-95, synapsin, VGlut, and NMDA receptor subunit 2A was observed in mouse hippocampal slices treated with junicedric acid. This cascade of events may be associated with the regulation of kinases, e.g., protein kinase C (PKC) and calcium/calmodulin-dependent protein kinase II (CaMKII), in addition to the activation of the canonical Wnt signaling pathway and could thus provide protection against Aβ oligomers, which trigger synaptic dysfunction. Our results suggest a potential neuroprotective role for diterpenes against the Aβ oligomers-induced neurodegenerative alterations, which make them interesting molecules to be further studied in the context of AD. [ABSTRACT FROM AUTHOR]

Alzheimer's disease ( AD) is the most common neurodegenerative disorder and the leading cause of age-related dementia worldwide. Several models for AD have been developed to provide information regarding the initial changes that lead to degeneration. Transgenic mouse models recapitulate many, but not all, of the features of AD, most likely because of the high complexity of the pathology. In this context, the validation of a wild-type animal model of AD that mimics the neuropathological and behavioral abnormalities is necessary. In previous studies, we have reported that the Chilean rodent O ctodon degus could represent a natural model for AD. In the present work, we further describe the age-related neurodegeneration observed in the O . degus brain. We report some histopathological markers associated with the onset progression of AD, such as glial activation, increase in oxidative stress markers, neuronal apoptosis and the expression of the peroxisome proliferative-activated receptor γ coactivator-1α ( PGC-1α). With these results, we suggest that the O . degus could represent a new model for AD research and a powerful tool in the search for therapeutic strategies against AD. [ABSTRACT FROM AUTHOR]