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DOI 10.1007/164_2021_532
WNT Signaling Is a Key Player in Alzheimer's Disease
2021
Inestrosa, Nibaldo C.
;
Tapia-Rojas, Cheril
;
Cerpa, Waldo
;
Cisternas, Pedro
;
Zolezzi Moraga, Juan Manuel
The cellular processes regulated by WNT signaling have been mainly studied during embryonic development and cancer. In the last two decades, the role of WNT in the adult central nervous system has been the focus of interest in our laboratory. In this chapter, we will be summarized beta-catenin-dependent and -independent WNT pathways, then we will be revised WNT signaling function at the pre- and post-synaptic level. Concerning Alzheimer's disease (AD) initially, we found that WNT/beta-catenin signaling activation exerts a neuroprotective mechanism against the amyloid beta (A beta) peptide toxicity. Later, we found that WNT/beta-catenin participates in Tau phosphorylation and in learning and memory. In the last years, we demonstrated that WNT/beta-catenin signaling is instrumental in the amyloid precursor protein (APP) processing and that WNT/beta-catenin dysfunction results in A beta production and aggregation. We highlight the importance of WNT/beta-catenin signaling dysfunction in the onset of AD and propose that the loss of WNT/beta-catenin signaling is a triggering factor of AD. The WNT pathway is therefore positioned as a therapeutic target for AD and could be a valid concept for improving AD therapy. We think that metabolism and inflammation will be relevant when defining future research in the context of WNT signaling and the neurodegeneration associated with AD.
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DOI 10.1007/164_2021_532
WNT Signaling Is a Key Player in Alzheimer's Disease
2021
Inestrosa, Nibaldo C.
;
Tapia-Rojas, Cheril
;
Cerpa, Waldo
;
Cisternas, Pedro
;
Zolezzi Moraga, Juan Manuel
The cellular processes regulated by WNT signaling have been mainly studied during embryonic development and cancer. In the last two decades, the role of WNT in the adult central nervous system has been the focus of interest in our laboratory. In this chapter, we will be summarized beta-catenin-dependent and -independent WNT pathways, then we will be revised WNT signaling function at the pre- and post-synaptic level. Concerning Alzheimer's disease (AD) initially, we found that WNT/beta-catenin signaling activation exerts a neuroprotective mechanism against the amyloid beta (A beta) peptide toxicity. Later, we found that WNT/beta-catenin participates in Tau phosphorylation and in learning and memory. In the last years, we demonstrated that WNT/beta-catenin signaling is instrumental in the amyloid precursor protein (APP) processing and that WNT/beta-catenin dysfunction results in A beta production and aggregation. We highlight the importance of WNT/beta-catenin signaling dysfunction in the onset of AD and propose that the loss of WNT/beta-catenin signaling is a triggering factor of AD. The WNT pathway is therefore positioned as a therapeutic target for AD and could be a valid concept for improving AD therapy. We think that metabolism and inflammation will be relevant when defining future research in the context of WNT signaling and the neurodegeneration associated with AD.
Scopus© Citations 24 2
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DOI 10.1007/s12035-019-01784-6
Andrographolide Reduces Neuroinflammation and Oxidative Stress in Aged Octodon degus
2020-02
Lindsay, Carolina B.
;
Zolezzi Moraga, Juan Manuel
;
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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DOI 10.1007/s12035-019-01784-6
Andrographolide Reduces Neuroinflammation and Oxidative Stress in Aged Octodon degus
2020-02
Lindsay, Carolina B.
;
Zolezzi Moraga, Juan Manuel
;
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.
Scopus© Citations 42 2
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DOI 10.1007/978-3-030-58814-4_63
Error Correction in Nanopore Reads for de novo Genomic Assembly
2020
Aldridge-Aguila, Jacqueline
;
Alvarez-Saravia, Diego
;
Navarrete Signorile, Marcelo Alejandro
;
Uribe Paredes, Roberto Alex
The purpose of genome sequencing is to determine the DNA sequence of a given organism. Current sequencing technologies can be classified by the type of output data. Whereas Nanopore technology generates long reads with high error rates, short read technologies - such as Illumina sequencing - generate shorter reads but with low error rate. Since de novo genome assembly of sequencing reads is defined as a NP-hard problem, it remains as one of the major challenges for defining reference genomes of different species. This paper aims to improve the quality of reads obtained through Oxford Nanopore Technologies (ONT). We developed an algorithm to associate the reads obtained from Illumina with the ones obtained with Nanopore. Low accuracy ONT reads were corrected with the high quality Illumina reads to achieve an improved sequencing data. The inclusion of this algorithm as a preprocessing step resulted in improved coverage, contig length, and mismatch rate when performing de novo genome assembly of a bacterial genome with well known tools.
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DOI 10.1007/978-3-030-17938-0_27
Identification of Immunoglobulin Gene Usage in Immune Repertoires Sequenced by Nanopore Technology
2019
Ahumada-Garcia, Roberto
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Gonzalez-Puelma, Jorge
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Alvarez-Saravia, Diego
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Barrientos, Ricardo J.
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Uribe Paredes, Roberto Alex
;
Lopez-Cortes, Xaviera A.
;
Navarrete Signorile, Marcelo Alejandro
The immunoglobulin receptor represents a central molecule in acquired immunity. The complete set of immunoglobulins present in an individual is known as immunological repertoire. The identification of this repertoire is particularly relevant in immunology and cancer research and diagnostics. In a seminal work we provided a proof of concept of the novel ARTISAN-PCR amplification method, we adapted this technology for sequencing using Nanopore technology. This approach may represent a faster, more portable and costeffective alternative to current methods. In this study we present the pipeline for the analysis of immunological repertoires obtained by this approach. This paper shows the performance of immune repertoires sequenced by Nanopore technology, using measures of error, coverage and gene usage identification. In the bioinformatic methodology used in this study, first, Albacore Base calling software, was used to translate the electrical signal of Nanopore to DNA bases. Subsequently, the sequons, introduced during amplification, were aligned using bl2seq from Blast. Finally, selected reads were mapped using IMGT/ HighV-QUEST and IgBlast. Our results demonstrate the feasibility of immune repertoire sequencing by Nanopore technology, obtaining higher depth than PacBio sequencing and better coverage than pair-end based technologies. However, the high rate of systematic errors indicates the need of improvements in the analysis pipeline, sequencing chemistry and/or molecular amplification.
Scopus© Citations 1 1
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DOI 10.1017/s0954579418001281
Physical and psychosocial development of Mapuche and nonindigenous Chilean toddlers: A modest role of ethnicity
2018-12
Navarrete Signorile, Marcelo Alejandro
;
Silva, Jaime R.
;
Van Ijzendoorn, Marinus H.
;
Carcamo, Rodrigo A.
Mapuche represents the largest indigenous group in Chile amounting to nearly 10% of the total population. In a longitudinal cohort of 12,398 children, we analyzed the role of ethnicity in physical and psychosocial development of Mapuche and nonindigenous Chilean toddlers (age 2.5 years), taking into account sociodemographic and caregiver characteristics. As indicated by our univariate analysis, the Mapuche developmental niche was characterized by lower income, lower maternal education, poorer quality of the home environment, longer breastfeeding, and higher parental stress. Physical development showed higher body mass index. Mapuche children showed less externalizing problems. We then analyzed the incremental contribution of ethnicity in a series of hierarchical regressions with the second wave of developmental measurements (age 4.5 years) as outcome variables, showing a significant but modest incremental contribution of ethnicity to the prediction of children's development between 2.5 and 4.5 years of age. Controlling for environmental variables, Mapuche showed less externalizing and internalizing, behavior problems. Socioeconomic status, quality of the home environment, and parenting stress were stronger predictors of socioemotional development than ethnicity per se.
Scopus© Citations 4 2
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DOI 10.3233/jad-170701
Neuroprotective Effects of Ferruginol, Jatrophone, and Junicedric Acid Against Amyloid-β Injury in Hippocampal Neurons
2018
Zolezzi Moraga, Juan Manuel
;
Lindsay, Carolina B.
;
Serrano, Felipe G.
;
Ureta, Roxana C.
;
Theoduloz, Cristina
;
Schmeda-Hirschmann, Guillermo
;
Inestrosa, Nibaldo C.
Soluble amyloid-beta (A beta) oligomers have been recognized as early neurotoxic intermediates with a key role in the synaptic dysfunction observed in Alzheimer's disease (AD). A beta oligomers block hippocampal long-term potentiation (LTP) and impair rodent spatial memory. Additionally, the presence of A beta 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 A beta peptide demonstrated that diterpenes, particularly ferruginol, restore LTP and reduce apoptosis. Recovery of the A beta 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 A beta oligomers, which trigger synaptic dysfunction. Our results suggest a potential neuroprotective role for diterpenes against the A beta oligomers-induced neurodegenerative alterations, which make them interesting molecules to be further studied in the context of AD.
Scopus© Citations 13 1
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DOI 10.1152/ajpheart.00710.2020
Paraquat herbicide diminishes chemoreflex sensitivity, induces cardiac autonomic imbalance and impair cardiac function in rats
2021-4
Pereyra, Katherin
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Schwarz, Karla G.
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Andrade, David C.
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Toledo, Camilo
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Rios-Gallardo, Angelica
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Diaz-Jara, Esteban
;
Bastias Candia, Sussy Del Carmen
;
Ortiz, Fernando C.
;
Ortolani, Domiziana
;
Del Rio, Rodrigo
Paraquat (PQT) herbicide is widely used in agricultural practices despite being highly toxic to humans. It has been proposed that PQT exposure may promote cardiorespiratory impairment. However, the physiological mechanisms involved in cardiorespiratory dysfunction following PQT exposure are poorly known. We aimed to determine the effects of PQT on ventilatory chemoreflex control, cardiac autonomic control, and cardiac function in rats. Male Sprague-Dawley rats received two injections/week of PQT (5 mg.kg(-1) ip) for 4 wk. Cardiac function was assessed through echocardiography and pressure-volume loops. Ventilatory function was evaluated using whole body plethysmography. Autonomic control was indirectly evaluated by heart rate variability (HRV). Cardiac electrophysiology (EKG) and exercise capacity were also measured. Four weeks of PQT administration markedly enlarged the heart as evidenced by increases in ventricular volumes and induced cardiac diastolic dysfunction. Indeed, end-diastolic pressure was significantly higher in PQT rats compared with control (2.42 +/- 0.90 vs. 4.01 +/- 0.92 mmHg, PQT vs. control, P < 0.05). In addition, PQT significantly reduced both the hypercapnic and hypoxic ventilatory chemoreflex response and induced irregular breathing. Also, PQT induced autonomic imbalance and reductions in the amplitude of EKG waves. Finally, PQT administration impaired exercise capacity in rats as evidenced by a similar to 2-fold decrease in times-to-fatigue compared with control rats. Our results showed that 4 wk of PQT treatment induces cardiorespiratory dysfunction in rats and suggests that repetitive exposure to PQT may induce harmful mid/long-term cardiovascular, respiratory, and cardiac consequences. NEW & NOREWORTHY Paraquat herbicide is still employed in agricultural practices in several countries. Here, we showed for the first time that 1 mo paraquat administration results in cardiac adverse remodeling, blunts ventilatory chemoreflex drive, and promotes irregular breathing at rest in previously healthy rats. In addition, paraquat exposure induced cardiac autonomic imbalance and cardiac electrophysiology alterations. Lastly, cardiac diastolic dysfunction was overt in rats following 1 mo of paraquat treatment.
Scopus© Citations 8 3
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DOI 10.1016/j.mad.2020.111250
Redox modifications in synaptic components as biomarkers of cognitive status, in brain aging and disease
2020-7
Munoz, Pablo
;
Ardiles, Alvaro O.
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Perez-Espinosa, Boris
;
Nuñez Espinosa, Cristian Andrés
;
Paula-Lima, Andrea
;
Gonzalez-Billault, Christian
;
Espinosa Parrilla, Maria Yolanda
Aging is a natural process that includes several changes that gradually make organisms degenerate and die. Harman's theory proposes that aging is a consequence of the progressive accumulation of oxidative modifications mediated by reactive oxygen/nitrogen species, which plays an essential role in the development and progression of many neurodegenerative diseases. This review will focus on how abnormal redox modifications induced by age impair the functionality of neuronal redox-sensitive proteins involved in axonal elongation and guidance, synaptic plasticity, and intercellular communication. We will discuss post-transcriptional regulation of gene expression by microRNAs as a mechanism that controls the neuronal redox state. Finally, we will discuss how some brain-permeant antioxidants from the diet have a beneficial effect on cognition. Taken together, the evidence revised here indicates that oxidative-driven modifications of specific proteins and changes in microRNA expression may be useful biomarkers for aging and neurodegenerative diseases. Also, some specific antioxidant therapies have undoubtedly beneficial neuroprotective effects when administered in the correct doses, in the ideal formulation combination, and during the appropriate therapeutic window. The use of some antioxidants is, therefore, still poorly explored for the treatment of neurodegenerative diseases such as Alzheimer's disease.
Scopus© Citations 14 1

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