Estrogen actions on glial reactivity and inflammation-mediated memory impairment: sex differences and interaction with other neurotrophic factors

There is growing evidence that documents profound effects of estrogens on learning, memory, and mood as well as neurodevelopment and neurodegenerative diseases. However, the ability of estradiol to influence synaptic plasticity, neurotransmission, neurodegeneration and cognition, could be different depending on sex dimorphisms. It emerges that estrogens have different, even opposite, effects as well as similar effects in male and female brains. The protective effects of estradiol on neural cells are mediated in part by modulation of neurotrophic factors such as insulin like growth factor (IGF-l), tyrosine kinase A (Trk A), nerve growth factors (NGF), and the like. Also, it modulates the action of neurotrophins, which in turn regulate the synaptogenesis, synaptic plasticity and synaptic functions. By these actions estrogen prevents or slows down the neurodegenerative process. Another described effect of estradiol is the capacity to modulate inflammatory response mediated by glial cells. Neuroinflammation is a feature not only of many neurological disorders but also of aging, and it is accompanied by activation of glial cells and the release of proinflammatory cytokines and chemokines. Such activation is a normal response oriented to protect neural tissue. However, excessive and chronic activation of glia may lead to neurotoxicity and may be harmful for neural tissue. Estrogenic compounds may be candidates to counteract brain inflammation under neurodegenerative conditions by targeting the production and release of proinflammatory molecules by glial cells. In this chapter we will review different mechanisms that may be implicated in the diverse actions of estradiol, the differences according to gender and we empathize in the anti-inflammatory action on glial cell. We will also explore the interaction of estradiol with others neurotrophic factors, such as IGF-I in the regulation of neurodegeneration and memory impairment. Finally, the possibility of using selective estrogen receptor modulators (SERMs) to exert estradiollike neuroprotective actions in the brain as an alternative to estrogen will be discussed.Instituto de Investigaciones Bioquímicas de La Plat

The Effects of Copper Overloads on Cholesterol Metabolism, and its Potential Association with the Development of Alzheimer's-Type Neurodegeneration

La enfermedad de Alzheimer (AD) es una enfermedad progresiva de etiología multifactorial y aparición espontánea e idiopática. Sus características neuropatológicas incluyen el depósito extracelular de placas β-amiloides (Aβ) e intracelular de la proteína Tau hiperfosforilada en hipocampo y corteza. Una de las teorías que predomina es la falla en el metabolismo de la proteína precursora amiloide (APP) produciendo aumentos del péptido β-amiloide 1-42 (Aβ1-42). Se ha demostrado que las enzimas β-y γ-secretasas están asociadas a rafts de Cho en las membranas, favoreciendo el aumento de la actividad de las mismas (Xiong et al., 2008). Existeuna asociación entre los niveles de Cho y el desarrollo de AD (Ricciarelli et al., 2012; Zhang y Liu, 2015). El Cho presente en el cerebro tiene un origen independiente respecto al Cho presente en otros tejidos, estando separados por la barrera hematoencefálica (BHE) (Zhang y Liu, 2015). En el cerebro adulto son los astrocitos los responsables de sintetizar y proveer de Cho a las neuronas (Niewig et al., 2009).Universidad Nacional de La Plat

EFECTOS DE SOBRECARGAS DE COBRE SOBRE EL METABOLISMO DEL COLESTEROL, Y SU POSIBLE VINCULACIÓN CON EL DESARROLLO DE NEURODEGENERACIÓN DE TIPO ALZHEIMER

La enfermedad de Alzheimer (AD) es una enfermedad progresiva de etiología multifactorial y aparición espontánea e idiopática. Sus características neuropatológicas incluyen el depósito extracelular de placas β-amiloides (Aβ) e intracelular de la proteína Tau hiperfosforilada en hipocampo y corteza. Una de las teorías que predomina es la falla en el metabolismo de la proteína precursora amiloide (APP) produciendo aumentos del péptido β-amiloide 1-42 (Aβ1-42). Se ha demostrado que las enzimas β- y γ- secretasas están asociadas a rafts de Cho en las membranas, favoreciendo el aumento de la actividad de las mismas (Xiong et al., 2008). Existe una asociación entre los niveles de Cho y el desarrollo de AD (Ricciarelli et al., 2012; Zhang y Liu, 2015). El Cho presente en el cerebro tiene un origen independiente respecto al Cho presente en otros tejidos, estando separados por la barrera hematoencefálica (BHE) (Zhang y Liu, 2015). En el cerebro adulto son los astrocitos los responsables de sintetizar y proveer de Cho a las neuronas (Niewig et al., 2009).  Por otro lado, se conoce que los iones Cu se hallan involucrados en la etiopatogénesis de la AD (Sparks y Schreurs, 2003; Squitti et al., 2005; Arnal et al., 2010a). se ha demostrado tanto in vivo como in vitro que aumentos en la concentración de este metal producen alteraciones en el SDA y aumentos en los marcadores de estrés oxidativo/nitrativo (Arnal et al., 2012, 2013b, 2014). En un modelo in vivo de ratas Wistar se observó aumento tanto los niveles de Cu plasmáticos como los del cerebro en relación con la dosis aplicada, demostrando que el Cu es capaz de atravesar la BHE y llegar al cerebro. Además, también aumentaron los niveles de Cho en ambas zonas (Arnal et al., 2014).  Finalmente, es sabido que los pacientes con AD presentan inflamación crónica con aumento en la producción de citoquinas pro-inflamatorias (Bermejo et al., 2008). A su vez, se ha descripto que aumentan los niveles de IL1β en astrocitos luego de su exposición a Aβ-42 (Van Gijsel-Bunnello et al., 2017). El factor IGF-I puede producirse localmente en el cerebro o ser transportado activamente hacia él y se ha demostrado que incrementa la supervivencia celular de cultivos primarios de neuronas hipotalámicas (Knusel et al., 1990). Es un potente neuroprotector que disminuye la inflamación del cerebro y reduce la astrocitosis (Fernández et al., 1996). En concordancia, nosotros hemos demostrado que modula la respuesta inflamatoria en cultivos de astrocitos tratados con LPS (Bellini et al., 2011).  Nuestra hipótesis de trabajo consiste en suponer que aumentos en la concentración de Cu podrían generar incrementos en los niveles de Cho y de esta manera aumentar los depósitos del mismo en las membranas. Esto, junto con los procesos de estrés oxidativo e inflamación que también podría generar el Cu, favorecería el desarrollo de una neurodegeneración de tipo AD. En este proyecto se propone utilizar cultivos primarios de astrocitos y neuronas. &nbsp

Restauration of age related motor impairment: role of IGF-1 based gene therapy and microglial activation

In the current study we implemented ICV IGF-1 gene therapy in very old rats (28 months) and assessed the motor performance pre and 17-days after surgery. Glial immunoreactivity in striatum was evaluated by Iba1 and GFAP markers.Facultad de Ciencias Médica

Aldehyde dehydrogenase 2 in the spotlight: the link between mitochondria and neurodegeneration

Growing body of evidence suggests that mitochondrial dysfunctions and resultant oxidative stress are likely responsible for many neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD). Aldehyde dehydrogenase (ALDH) superfamily plays a crucial role in several biological processes including development and detoxification pathways in the organism. In particular, ALDH2 is crucial in the oxidative metabolism of toxic aldehydes in the brain, such as catecholaminergic metabolites (DOPAL and DOPEGAL) and the principal product of lipid peroxidation process 4-HNE. This review aims to deepen the current knowledge regarding to ALDH2 function and its relation with brain-damaging processes that increase the risk to develop neurodegenerative disorders. We focused on relevant literature of what is currently known at molecular and cellular levels in experimental models of these pathologies. The understanding of ALDH2 contributions could be a potential target in new therapeutic approaches for PD and AD due to its crucial role in mitochondrial normal function maintenance that protects against neurotoxicity.Instituto de Investigaciones Bioquímicas de La Plat

Influence on effectiveness of early treatment with anti-TNF therapy in rheumatoid arthritis

Purpose. To evaluate the association between starting early treatment with anti-TNF and effectiveness as well as the possibility of applying therapeutic spacing in daily practice in patients with rheumatoid arthritis (RA). Methods. Observational, retrospective study conducted in two universitary hospitals in Spain. RA patients who received the first anti-TNF (adalimumab: ADA, etanercept: ETN or infliximab: IFX) during the study period (October 2006-2010) were included. Demographic data, time since diagnosis, disease activity (DAS28-ESR) and anti-TNF dosage were analyzed. Therapeutic objective was defined as DAS28<2.6. Also the response related to criteria of the European League Against Rheumatism (EULAR) was evaluated. Therapeutic spacing was defined as the use of a lower dose or a higher interval according to label doses. The main endpoint was to assess the association between the effectiveness and the moment when the anti-TNF therapy begins. The secondary target was to evaluate the association between RA activity at the beginning of treatment with anti-TNF and dose used. Results. 82 patients were included. The prescription profile was: ADA (48.8%), ETN (31.7%) and IFX (19.5%). 71.4% of patients treated with anti-TNF during the first year since diagnosis, 57.1% of those who started after 1-5 years and 30.6% of patients who started after 5 years were in remission when the study ended. De-escalation strategy was performed in 25.6% of patients: ETN (38.5%), ADA (20.0%) and IFX (18.8%). The patients treated with a higher dose according to label doses were: IFX (81%), ADA, (12.5%) and ETN (7.7%). Conclusions. Results suggest that early treatment with anti-TNF can achieve a higher percentage of remissions. Therapeutic spacing is established as a strategy that improves the efficiency in those patients in remission, being the ETN the anti-TNF most susceptible for spacing, although a relation between the early beginning with anti-TNF and the used dose was not found.Instituto de Investigaciones Bioquímicas de La Plat

Influence on effectiveness of early treatment with anti-TNF therapy in rheumatoid arthritis

Purpose. To evaluate the association between starting early treatment with anti-TNF and effectiveness as well as the possibility of applying therapeutic spacing in daily practice in patients with rheumatoid arthritis (RA). Methods. Observational, retrospective study conducted in two universitary hospitals in Spain. RA patients who received the first anti-TNF (adalimumab: ADA, etanercept: ETN or infliximab: IFX) during the study period (October 2006-2010) were included. Demographic data, time since diagnosis, disease activity (DAS28-ESR) and anti-TNF dosage were analyzed. Therapeutic objective was defined as DAS28<2.6. Also the response related to criteria of the European League Against Rheumatism (EULAR) was evaluated. Therapeutic spacing was defined as the use of a lower dose or a higher interval according to label doses. The main endpoint was to assess the association between the effectiveness and the moment when the anti-TNF therapy begins. The secondary target was to evaluate the association between RA activity at the beginning of treatment with anti-TNF and dose used. Results. 82 patients were included. The prescription profile was: ADA (48.8%), ETN (31.7%) and IFX (19.5%). 71.4% of patients treated with anti-TNF during the first year since diagnosis, 57.1% of those who started after 1-5 years and 30.6% of patients who started after 5 years were in remission when the study ended. De-escalation strategy was performed in 25.6% of patients: ETN (38.5%), ADA (20.0%) and IFX (18.8%). The patients treated with a higher dose according to label doses were: IFX (81%), ADA, (12.5%) and ETN (7.7%). Conclusions. Results suggest that early treatment with anti-TNF can achieve a higher percentage of remissions. Therapeutic spacing is established as a strategy that improves the efficiency in those patients in remission, being the ETN the anti-TNF most susceptible for spacing, although a relation between the early beginning with anti-TNF and the used dose was not found.Instituto de Investigaciones Bioquímicas de La Plat

Restauración de la disminución motora asociada a la edad mediante la activación de la microglía por terapia génica para IGF-I

En estudios previamente realizados por nuestro grupo hemos descripto que la terapia génica intracerebroventricular (ICV) para IGF-I induce un significativo aumento del desempeño motor en ratas seniles. Las células de la microglía son esenciales para asegurar la neuroprotección del sistema nervioso central, tanto en condiciones normales como patológicas. Estas células representan una fuente importante de factores neurotróficos y se ha descripto que la capacidad neuroprotectora de las mismas disminuye con el envejecimiento cerebral. Numerosos trabajos demuestran que el IGF-I estimula la proliferación de la microglía.Facultad de Ciencias Médica

Estradiol activates PI3K/Akt/GSK3 pathway under chronic neurodegenerative conditions triggered by perinatal asphyxia

Perinatal asphyxia (PA) remains as one of the most important causes of short-term mortality, psychiatric and neurological disorders in children, without an effective treatment. In previous studies we have observed that the expression of different neurodegenerative markers increases in CA1 hippocampal area of 4-months-old male rats born by cesarean section and exposed for 19 min to PA. We have also shown that a late treatment with 17β estradiol (daily dose of 250 μg/kg for 3 days) was able to revert the brain alterations observed in those animals. Based on these previous results, the main aim of the present study was to explore the mechanism by which the estrogenic treatment is involved in the reversion of the chronic neurodegenerative conditions induced by PA. We demonstrated that estradiol treatment of adult PA exposed animals induced an increase in estrogen receptor (ER) a and insulin-like growth factor receptor (IGF-1R) protein levels, an activation of the phosphatidylinositol 3-kinase/Akt/glycogen synthase kinase 3 beta/β-catenin signaling pathway and an increase in Bcl-2/Bax ratio in the hippocampus in comparison to PA exposed animals treated with vehicle. Taking together, our data suggest that the interaction between ERa and IGF-IR, with the subsequent downstream activation, underlies the beneficial effects of estradiol observed in late treatment of PA.Instituto de Investigaciones Bioquímicas de La Plat

Insulin-like growth factor-I gene delivery to astrocytes reduces their inflammatory response to lipopolysaccharide

Background: Insulin-like growth factor-I (IGF-I) exerts neuroprotective actions in the central nervous system that are mediated at least in part by control of activation of astrocytes. In this study we have assessed the efficacy of exogenous IGF-I and IGF-I gene therapy in reducing the inflammatory response of astrocytes from cerebral cortex. Methods: An adenoviral vector harboring the rat IGF-I gene and a control adenoviral vector harboring a hybrid gene encoding the herpes simplex virus type 1 thymidine kinase fused to Aequorea victoria enhanced green fluorescent protein were used in this study. Primary astrocytes from mice cerebral cortex were incubated for 24 h or 72 h with vehicle, IGF-I, the IGF-I adenoviral vector, or control vector; and exposed to bacterial lipopolysaccharide to induce an inflammatory response. IGF-I levels were measured by radioimmunoassay. Levels of interleukin 6, tumor necrosis factor-α, interleukin-1β and toll-like receptor 4 mRNA were assessed by quantitative real-time polymerase chain reaction. Levels of IGF-I receptor and IGF binding proteins 2 and 3 were assessed by western blotting. The subcellular distribution of nuclear factor κB (p65) was assessed by immunocytochemistry. Statistical significance was assessed by one way analysis of variance followed by the Bonferroni pot hoc test. Results: IGF-I gene therapy increased IGF-I levels without affecting IGF-I receptors or IGF binding proteins. Exogenous IGF-I, and IGF-I gene therapy, decreased expression of toll-like receptor 4 and counteracted the lipopolysaccharide-induced inflammatory response of astrocytes. In addition, IGF-I gene therapy decreased lipopolysaccharide-induced translocation of nuclear factor κB (p65) to the cell nucleus. Conclusion: These findings demonstrate efficacy of exogenous IGF-I and of IGF-I gene therapy in reducing the inflammatory response of astrocytes. IGF-I gene therapy may represent a new approach to reduce inflammatory reactions in glial cells.Facultad de Ciencias Médica