Biological basis for cerebral dysfunction in schizophrenia in contrast with Alzheimer’s disease

Schizophrenia and Alzheimer’s disease are two disorders that, while conceptualized as pathophysiologically and clinically distinct, cause substantial cognitive and behavioral impairment worldwide, and target apparently similar – or nearby – circuitry in regions such as the temporal and frontal lobes.We review the salient differences and similarities from selected historical, nosological, and putative mechanistic viewpoints, as a means to help both clinicians and researchers gain a better insight into these intriguing disorders, for which over a century of research and decades of translational development was needed to begin yielding treatments that are objectively effective, but still very far from entirely satisfactory. Ongoing comparison and “cross-pollination” among these approaches to disorders that produce similar deficits is likely to continue improving both our insight into the mechanisms at play, and the development of biotechnological approaches to tackle both conditions – and related disorders – more rapidly and efficaciously

Toxicidad metabólica y resistencia a insulina por antipsicóticos : efectos en el músculo esquelético

Uno de los efectos secundarios más severos de los antipsicóticos de segunda generación es la toxicidad metabólica, que afecta a millones de individuos a nivel mundial. Al respecto, se ha descrito que Olanzapina (OLZ) produce resistencia a insulina y Diabetes tipo II en periodos tan cortos como 12 semanas. Los mecanismos a través de los cuales OLZ causa estos efectos no se han dilucidado completamente, estudios postulan efectos a nivel central y periférico, sin abordar los mecanismos de toxicidad en músculo esquelético. Para el desarrollo de esta investigación se utilizó la línea celular L6 de músculo de rata neonata, pre incubada con OLZ 50 μg/mL por 24 h e Insulina 100 nM por 3h. Ensayos realizados mediante citometría de flujo y microscopía confocal muestran que OLZ impide la captación de glucosa inducida por Insulina en células L6. Estos resultados indican que la toxicidad metabólica de OLZ, va más allá de los efectos en el sistema nervioso, afectando la respuesta fisiológica del tejido muscular estriadoFil: Salamanca, Catalina. Universidad de Santiago de ChileFil: Bustos, Catalina . Universidad de Santiago de ChileFil: Díaz, Francisco . Universidad de ChileFil: Troncoso, Rodrigo . Universidad de ChileFil: Del Campo, Andrea . Universidad de Santiago de ChileFil: Rojo, Leonel E. . Universidad de Santiago de Chil

P2X7 receptor is essential for cross-dressing of bone marrow-derived dendritic cells

T cell activation requires the processing and presentation of antigenic peptides in the context of a major histocompatibility complex (MHC complex). Cross-dressing is a non-conventional antigen presentation mechanism, involving the transfer of preformed peptide/MHC complexes from whole cells, such as apoptotic cells (ACs) to the cell membrane of professional antigen-presenting cells (APCs), such as dendritic cells (DCs). This is an essential mechanism for the induction of immune response against viral antigens, tumors, and graft rejection, which until now has not been clarified. Here we show for first time that the P2X7 receptor (P2X7R) is crucial to induce cross-dressing between ACs and Bone-Marrow DCs (BMDCs). In controlled ex vivo assays, we found that the P2X7R in both ACs and BMDCs is required to induce membrane and fully functional peptide/MHC complex transfer to BMDCs. These findings show that acquisition of ACs-derived preformed antigen/MHC-I complexes by BMDCs requires P2X7R expression.Fil: Barrera Avalos, Carlos. Universidad de Santiago de Chile; ChileFil: Briceño, Pedro. Universidad de Chile; ChileFil: Valdés, Daniel. Universidad de Santiago de Chile; ChileFil: Imarai, Mónica. Universidad de Santiago de Chile; ChileFil: Leiva Salcedo, Elías. Universidad de Santiago de Chile; ChileFil: Rojo, Leonel E.. Universidad de Santiago de Chile; ChileFil: Milla, Luis A.. Universidad de Santiago de Chile; ChileFil: Huidobro Toro, Juan Pablo. Universidad de Santiago de Chile; ChileFil: Robles Planells, Claudia. Universidad de Santiago de Chile; ChileFil: Escobar, Alejandro. Universidad de Chile; ChileFil: Di Virgilio, Francesco. Università di Ferrara; ItaliaFil: Moron, Victor Gabriel. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Bioquímica Clínica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Sauma, Daniela. Universidad de Chile; ChileFil: Acuña Castillo, Claudio. Universidad de Santiago de Chile; Chil

Metabolic Syndrome and Antipsychotics: The Role of Mitochondrial Fission/Fusion Imbalance

Second-generation antipsychotics (SGAs) are known to increase cardiovascular risk through several physiological mechanisms, including insulin resistance, hepatic steatosis, hyperphagia, and accelerated weight gain. There are limited prophylactic interventions to prevent these side effects of SGAs, in part because the molecular mechanisms underlying SGAs toxicity are not yet completely elucidated. In this perspective article, we introduce an innovative approach to study the metabolic side effects of antipsychotics through the alterations of the mitochondrial dynamics, which leads to an imbalance in mitochondrial fusion/fission ratio and to an inefficient mitochondrial phenotype of muscle cells. We believe that this approach may offer a valuable path to explain SGAs-induced alterations in metabolic homeostasis

Selective interaction of lansoprazole and Astemizole with tau polymers: Potential new clinical use in diagnosis of Alzheimer's disease

We describe the interactions of two benzimidazole derivatives, astemizole (AST) and lansoprazole (LNS), with anomalous aggregates of tau protein (neurofibrillary tangles). Interestingly, these compounds, with important medical applications in the treatment of allergies and gastrointestinal disorders respectively, specifically bind to aggregated variants of tau protein and to paired helical filaments isolated from brains of Alzheimer's disease (AD) patients. These ligands appear to be a powerful tool to tag brain-isolated tau-aggregates and heparin-induced polymers of recombinant tau. The interactions of AST and LNS with tau aggregates were assessed by classical radioligand assays, surface plasmon resonance, and bioinformatic approaches. The affinity of AST and LNS for tau aggregates was comparatively higher than that for amyloid-β polymers according to our data. This is relevant since senile plaques are also abundant but are not pathognomonic in AD patients. Immunochemical studies on

Mifepristone for treatment of metabolic syndrome: beyond cushing’s syndrome

A growing body of research indicates that cortisol, the glucocorticoid product of the activation of the hypothalamic-pituitary-adrenal axis, plays a role in the pathophysiology of metabolic syndrome. In this regard, chronic exposure to cortisol is associated with risk factors related to metabolic syndrome like weight gain, type 2 diabetes, hypertension, among others. Mifepristone is the only FDA-approved drug with antiglucocorticoids properties for improved the glycemic control in patients with type 2 patients secondary to endogenous Cushing's syndrome. Mifepristone also have been shown positive effects in rodents models of diabetes and patients with obesity due to antipsychotic treatment. However, the underlying molecular mechanisms are not fully understood. In this perspective, we summarized the literature regarding the beneficial effects of mifepristone in metabolic syndrome from animal studies to clinical research. Also, we propose a potential mechanism for the beneficial effects in insulin sensitivity which involved the regulation of mitochondrial function in muscle cells.Enlace FONDECYT-VID: EN29/18 Comisión Nacional de Investigación Cientifica y Tecnológica (CONICYT) CONICYT FONDECYT 1191078 11190756 FONDAP 1513001

Neuroinflammation: Implications for the Pathogenesis and Molecular Diagnosis of Alzheimer's Disease

During the past few years, an increasing set of evidence has supported the major role of deregulation of the interaction patterns between glial cells and neurons in the pathway toward neuronal degeneration. Neurons and glial cells, together with brain vessels, constitute an integrated system for brain function. Inflammation is a process related with the onset of several neurodegenerative disorders, including Alzheimer's disease (AD). Several hypotheses have been postulated to explain the pathogenesis of AD, but none provides insight into the early events that trigger metabolic and cellular alterations in neuronal degeneration. The amyloid hypothesis was sustained on the basis that Aβ-peptide deposition into senile plaques is responsible for neurodegeneration. However, recent findings point to Aβ oligomers as responsible for synaptic impairment in neuronal degeneration. Amyloid is only one among many other major factors affecting the quality of neuronal cells. Another explanation deriv

Metabolic syndrome and antipsychotics: The role of mitochondrial fission/fusion imbalance

Second-generation antipsychotics (SGAs) are known to increase cardiovascular risk through several physiological mechanisms, including insulin resistance, hepatic steatosis, hyperphagia, and accelerated weight gain. There are limited prophylactic interventions to prevent these side effects of SGAs, in part because the molecular mechanisms underlying SGAs toxicity are not yet completely elucidated. In this perspective article, we introduce an innovative approach to study the metabolic side effects of antipsychotics through the alterations of the mitochondrial dynamics, which leads to an imbalance in mitochondrial fusion/fission ratio and to an inefficient mitochondrial phenotype of muscle cells. We believe that this approach may offer a valuable path to explain SGAs-induced alterations in metabolic homeostasis.Proyecto Fondecyt Iniciacion of CONICYT, Chile 1114091

N-Acetyl cysteine and catechin-Derived polyphenols: A path toward multi-target compounds against alzheimer's disease

Background: Alzheimer's disease (AD) is a multifactorial disease, that involves neuroinflammatory processes in which microglial cells respond to "damage signals". The latter includes oligomeric tau, iron, oxidative free radicals, and other molecules that promotes neuroinflammation in the brain, promoting neuronal death and cognitive impairment. Since AD is the first cause of dementia in the elderly, and its pharmacotherapy has limited efficacy, novel treatments are critical to improve the quality of life of AD patients. Multitarget therapy based on nutraceuticals has been proposed as a promising intervention based on evidence from clinical trials. Several studies have shown that epicatechin-derived polyphenols from tea improve cognitive performance; also, the polyphenol molecule N-acetylcysteine (NAC) promotes neuroprotection. Objective: To develop an approach for a rational design of leading compounds against AD, based on specific semisynthetic epicatechin and catechin derivatives. Methods: We evaluated tau aggregation in vitro and neuritogenesis by confocal microscopy in mouse neuroblastoma cells (N2a), after exposing cells to either epicatechin-pyrogallol (EPIC-PYR), catechin-pyrogallol (CAT-PYR), catechin-phloroglucinol (CAT-PhG), and NAC. Results: We found that EPIC-PYR, CAT-PYR, and CAT-PhG inhibit human tau aggregation and significantly increase neuritogenesis in a dose-dependent manner. Interestingly, modification with a phloroglucinol group yielded the most potent molecule of those evaluated, suggesting that the phloroglucinol group may enhance neuroprotective activity of the catechin-derived compounds. Also, as observed with cathechins, NAC promotes neuritogenesis and inhibits tau self-aggregation, possibly through a different pathway. Conclusion: EPIC-PYR, CAT-PYR, CAT-PhG, and NAC increased the number of neurites in Na2 cell line and inhibits tau-self aggregation in vitro.Innova, High Technology Project CORFO 14IEAT-28658 International Center for Biomedicine (ICC) Ricardo B. Maccioni Foundation FONDEQUIP EQM15002