Dancing with glia: The role of astrocytes, microglia and oligodendrocytes and their relation with neurons in neuroinflammation and aging

This review provides an original overview of glial cells functions on the central nervous system and their relationship withneuroinflammation. We decided to correlate astrocytes, microglia and oligodendrocytes functions with neurons interplay, and refer it toTango genre and dance. Furthermore, this revision summarizes studies that support the roles of glial cells in neuroinflammation underdifferent conditions, such as aging and main neurodegenerative diseases in particular, Parkinson?s Disease and Alzheimer?s Disease.Fil: Herrera, Macarena Lorena. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Farmacología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Farmacología Experimental de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Instituto de Farmacología Experimental de Córdoba; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner". Universidad Nacional de la Plata. Facultad de Ciencias Médicas. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner"; ArgentinaFil: Dolcetti, Franco Juan Cruz. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner". Universidad Nacional de la Plata. Facultad de Ciencias Médicas. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner"; ArgentinaFil: Falomir Lockhart, Eugenia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner". Universidad Nacional de la Plata. Facultad de Ciencias Médicas. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner"; ArgentinaFil: Champarini, Leandro Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Farmacología Experimental de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Instituto de Farmacología Experimental de Córdoba; Argentina. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Farmacología; ArgentinaFil: Pennini, Jeronimo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner". Universidad Nacional de la Plata. Facultad de Ciencias Médicas. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner"; ArgentinaFil: Hereñú, Claudia Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Farmacología Experimental de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Instituto de Farmacología Experimental de Córdoba; Argentina. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Farmacología; ArgentinaFil: Bellini, Maria Jose. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner". Universidad Nacional de la Plata. Facultad de Ciencias Médicas. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner"; Argentin

Cognitive impairment in Parkinson's disease: the hippocampus role

La enfermedad de Parkinson es una enfermedad neurodegenerativa de las neuronas dopaminérgicas de la vía nigrosestriatal. Es considerada de índole multifactorial debido a la multiplicidad de síntomas que experimentan los pacientes, los cuales pueden agruparse por su afección de las vías motoras y/o de las vías mesolímibicas. Si bien esta patología es conocida por sus déficits motores característicos, los pacientes también presentan una amplia variedadde síntomas no motores, como deterioro del aprendizaje y la memoria, depresión, problemas gastrointestinales, entre otros, que afectan severamente su calidad de vida. Estos síntomas no motores resultan de una disfunción de sistemas interconectados, que incluyen al cuerpo estriado, la neocorteza y el hipocampo y de los diferentes circuitos glutamatérgicos involucrados en la modulación de la plasticidad sináptica. Es por esto que la presente revisión busca profundizar el conocimiento actual en relación al deterioro cognitivo asociado a la patología parkinsoniana para lograr un mejor entendimiento de los cambios neuronales, a nivel molecular, químico y fisiológico, principalmente en el hipocampo. El conocimiento de estos mecanismos no motores participantes en la EP podrían resultar en un potencial enfoque de nuevas estrategias terapéuticas.Parkinson’s disease is a neurodegenerative disorder that results from a progressive dopaminergic neuronal loss. It is considered a multifactorial condition due to the multiplicity of symptoms experienced by patients, which can be grouped by their disturbance in motor pathways and / or mesolímibics pathways. While this condition is known for its characteristic motor deficits, patients also have a wide variety of non-motor symptoms, such as impaired learning and memory, depression, gastrointestinal problems, among others, which severely affect their quality of life. These non-motor symptoms result from dysfunction of interconnected systems, including the striatum, the neocortex and the hippocampus and the different glutamatergic circuits involved in synaptic plasticity modulation. This review seeks to deepen the current knowledge regarding to cognitive impairment associated with parkinsonian pathology for a better understanding of the neural changes at molecular, chemical and physiological level, mainly in the hippocampus. Knowledge of these mechanisms involved in non-motor PD could result in potential new therapeutic strategies.Facultad de Ciencias MédicasInstituto de Investigaciones Bioquímicas de La Plat

Study of bacterial defined consortium adapted to low phenanthrene bioavailability

A general problem of bioremediation of polycyclic aromatic hydrocarbons (PAH) contaminated soil is that the degradation appears rather slow, due to the propensity of these nonpolar contaminants to adsorb strongly to organic matter. The establishment of microniches of PAH degrading bacteria in an aged PAH contaminated soil represents a process strongly influenced by the manner in which the PAH are exposure in the soil and bacterial capability to develop physiological strategies to adapt to the PAH bioavailability. Due to the reduced bioavailability, the bioaugmentation strategy with cultures obtained by enrichment in solid phase systems, could be a promising strategy to apply in aged contaminated soils. Applying an enrichment method with the phenanthrene provided in a sorbed state, a degrading consortia was previously obtained. The predominant strains from the consortia were isolated and identified as belonging to Sphingobium, Acidovorax, Rhodococcus and Arthrobacter genera (strains C1, C2, C3 and C4, respectively) suggesting that the strains could develop different strategies to integrate the degrader consortium. Because the successful of survival and establishment of a consortium in soil is probably higher than those obtained with the inoculation of only one strain, we focussed our study in understanding how a defined consortium built by these four strains could be more efficient in reducing sorbed phenanthene than pure cultures. The Amberlite® XAD-2 preloaded with phenanthrene (10.8mg of phenanthrene g-1 XAD2) was used as solid model in batch system with mineral medium (10% p/v). Each strain and the defined consortium were inoculated in the solid model in batch system with phenanthrene as only carbon source. Systems without phenanthere were inoculated to evaluate the inespecific adsortion to the resin beads. The biomass developed on the beads was monitoring by R2 agar count and FTIR spectroscopy (evaluating the increase in Amide I band at 1650cm-1) after 10 and 30 days of incubation at 28C. Only the Arthrobacter sp. C4 strain growing as pure culture exceeded the 106 ufc/g of XAD2-Phen after 10d. Both by plate count and FTIR we could determine that, C1 and C4 biomass obtained in pure cultures were more abundant on XAD2 beads than XAD2-Phen, suggesting the strains could degrade the resin. When the four strains were inoculated together in XAD2-Phen, each strain rose to 107 CFU/g and remained this value after 30d. Both the high amount of carbohydrates observed for Acidovorax sp. C2 strain (1200-900cm-1 and 3500cm-1) and the significant production of lipids for Rhodococcus sp. C3 strain (3000-2800 cm-1) could be detected in the defined consortium. These results demonstrated that at least these two strains could establish and express their phenotypes during the consortium development. Both FTIR spectroscopy and HPLC techniques allow the detection of phenanthrene by products accumulation along the pure cultures, which were reduced in the consortium

IGF1 Gene Therapy Modifies Microglia in the Striatum of Senile Rats

Microglial cells become dystrophic with aging; this phenotypic alteration contributes to basal central nervous system (CNS) neuroinflammation being a risk factor for age related neurodegenerative diseases. In previous studies we have observed that insulin like growth factor 1 (IGF1) gene therapy is a feasible approach to target brain cells, and that is effective to modify inflammatory response in vitro and to ameliorate cognitive or motor deficits in vivo. Based on these findings, the main aim of the present study is to investigate the effect of IGF1 gene therapy on microglia distribution and morphology in the senile rat. We found that IGF1 therapy leads to a region-specific modification of aged microglia population

Dancing with Glia: The Role of Astrocytes, Microglia and Oligodendrocytes and their Relation with Neurons in Neuroinflammation and Aging

This review provides an original overview of glial cells functions on the central nervous system and their relationship with neuroinflammation. We decided to correlate astrocytes, microglia and oligodendrocytes functions with neurons interplay, and refer it to Tango genre and dance. Furthermore, this revision summarizes studies that support the roles of glial cells in neuroinflammation under different conditions, such as aging and main neurodegenerative diseases in particular, Parkinson’s Disease and Alzheimer’s Disease.Instituto de Investigaciones Bioquímicas de La Plat

Implication of Oxidative Stress, Aging, and Inflammatory Processes in Neurodegenerative Diseases: Growth Factors as Therapeutic Approach

Oxidative stress (OS) is defined as the imbalance between the production of reactive oxygen species (ROS) and the antioxidant defense system. Living organisms produce ROS from molecular oxygen as a consequence of normal cellular metabolism. In order to prevent damage, cells have an antioxidant defense system constituted by an enzymatic component (including catalases, superoxide dismutases, etc.) and nonenzymatic antioxidants component (glutathione, α-tocopherol, ascorbic acid, etc.). When the levels of ROS exceed cell capacity, it can cause damage in cellular components such as carbohydrates, nucleic acids, lipids, and proteins, thus altering their function. Whenever this imbalance occurs within the central nervous system, it can lead to the development of the neurodegenerative disorders. Neurodegenerative diseases are characterized by the loss of neuronal cells and, in most cases, by the aggregates of proteins that form intracytoplasmic and intranuclear inclusions in neurons and glial cells. Data on the literature show that there are two possible mechanisms involved in most of neurodegenerative diseases: (1) mutations and/or aggregation of characteristic proteins of each disease such as α-synuclein in Parkinson’s disease (PD) or beta-amyloid peptide in Alzheimer’s disease (AD) and (2) dysfunction of mitochondrial energy metabolism in neurons. In this section, we will focus on this last one.Instituto de Investigaciones Bioquímicas de La Plat

IGF-1 Gene Therapy Modifies Inflammatory Environment and Gene Expression in the Caudate-Putamen of Aged Female Rat Brain

Brain aging is characterized by chronic neuroinflammation caused by activation of glial cells, mainly microglia, leading to alterations in homeostasis of the central nervous system. Microglial cells are constantly surveying their environment to detect and respond to diverse signals. During aging, microglia undergo a process of senescence, characterized by loss of ramifications, spheroid formation, and fragmented processes, among other abnormalities. Therefore, the study of microglia senescence is of great relevance to understand age‐related declines in cognitive and motor function.We have targeted the deleterious effects of aging by implementing gene therapy with IGF-1, employing recombinant adenoviral vectors (RAds) as a delivery system. In this study, we performed intracerebroventricular (ICV) IGF-1 gene therapy on aged female rats and evaluated its effect on Caudate-Putamen unit (CPu) gene expression and inflammatory state. IGF-1 gene therapy modified senescent microglia of the CPu towards an anti-inflammatory state increasing the proportion of Iba1+Arg1+ cells. Moreover, IGF-1 gene therapy was able to regulate the pro-inflammatory environment of CPu in female aged rats by down-regulating the expression of genes typically over-expressed during aging. Our results demonstrate that, ICV IGF-1 gene therapy, is capable to modulate microglia cells and CPu gene expression, leading to an improvement in motor function.Instituto de Investigaciones Bioquímicas de La Plat

Novel adenoviral IGF-1 administration modulates the association between depressive symptoms and aging: Does gender matter?

Depression is an illness of multifactorial origin and it seems to involve the dysregulation of many physiological processes. It also has been associated with age and a decreased in the expression of some neurotrophins. However, there are not unique animal models to assay depressive-like behavior, with male and females responding differently. In this study, we report the effects of gender on aged associated depressive signs as frailty, muscular strength and motor activity, as well as the role of intramuscular IGF-1 gene therapy in these processes. We found that male mice had higher general discomfort than females. Moreover, we observed that IGF-1 treatment did not modify this index in females. Regarding male mice, adenoviral IGF-1 injection reduced frailty scores compared to its adenoviral control. According to data, IGF-1 gene therapy had a positive effect on depressive associated hypo-locomotion activity as indicate by delta of total distance and the increment observed in time of mobility in male mice. This neurotrophic factor also increased the latency of time to fall in grip strength in male mice compared to female mice. Moreover, we observed that, while the therapy had no effect on the digging behavior, IGF-1 treatment diminished the latency to dig and increase the number of buried marbles in male mice, having no effect on female. The present study demonstrates that, in order to establish an animal model of depression both, gender and age are relevant variables/factors to consider. We also conclude that a frailty phenotype underlies depressive-like symptoms in an experimental mouse model. Furthermore, we demonstrated that intramuscular injection represents a less invasive, feasible and controllable route of IGF-1 gene delivery for the treatment of the depressive phenotype in old mice.Fil: Herrera, Macarena Lorena. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Farmacología Experimental de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Instituto de Farmacología Experimental de Córdoba; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner". Universidad Nacional de la Plata. Facultad de Ciencias Médicas. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner"; ArgentinaFil: Basmadjian, Osvaldo Martin. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Farmacología Experimental de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Instituto de Farmacología Experimental de Córdoba; ArgentinaFil: Falomir Lockhart, Eugenia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner". Universidad Nacional de la Plata. Facultad de Ciencias Médicas. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner"; ArgentinaFil: Dolcetti, Franco Juan Cruz. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner". Universidad Nacional de la Plata. Facultad de Ciencias Médicas. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner"; ArgentinaFil: Hereñú, Claudia Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Farmacología Experimental de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Instituto de Farmacología Experimental de Córdoba; ArgentinaFil: Bellini, Maria Jose. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner". Universidad Nacional de la Plata. Facultad de Ciencias Médicas. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner"; Argentin

Implication of oxidative stress, aging and inflammatory processes in neurodegenerative diseases: growth factors as therapeutic approach

The incidence of neurodegenerative diseases is increasing progressively, and unfortunately the molecular mechanisms that lead to them are still unknown. Several studies are advancing in the comprehension of the processes involved in the establishment of the neurodegeneration. In this sense, the current approaches are focus on genes associated with the neurodegenerative diseases, reactional gliosis or microglial activation, pro-inflammatory cytokines production, IL-6 increase as a transcription factor, growth factors decrease, mitochondrial dysfunction, antioxidant defense system, cellular metabolism, protein degradation/ aggregation and oxidative stress triggering redox-dependent signals among others. Parkinson and Alzheimer´s diseases show an increased diagnosis worldwide and are examples of deleterious effects associated with aging. The present chapter is focused on the implication of the oxidative stress, aging and inflammation processes on neurodegenerative alterations that lead to neuronal dysfunctions, tissue disturbances and motor-cognitive disorders. In regard to this, the neurotrophic factors of clinical interest prevent the degeneration and enhance recovery of remaining neurons. Among them, insulin-like growth factor 1 (IGF-1), which is strongly induced by microglial cells after different insults such as ischemia, cortical injury and inflammatory processes, is emerging as a powerful neuroprotective molecule. For this reason, we will close this chapter with the implications of IGF-1 on neurodegenerative diseases as a key neuroprotective and neuromodulator molecule.Fil: Herrera, Macarena Lorena. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Farmacología Experimental de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Instituto de Farmacología Experimental de Córdoba; ArgentinaFil: Falomir Lockhart, Eugenia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner". Universidad Nacional de la Plata. Facultad de Ciencias Médicas. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner"; ArgentinaFil: Dolcetti, Franco Juan Cruz. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner". Universidad Nacional de la Plata. Facultad de Ciencias Médicas. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner"; ArgentinaFil: Arnal, Nathalie. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner". Universidad Nacional de la Plata. Facultad de Ciencias Médicas. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner"; ArgentinaFil: Bellini, Maria Jose. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner". Universidad Nacional de la Plata. Facultad de Ciencias Médicas. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner"; ArgentinaFil: Hereñú, Claudia Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Farmacología Experimental de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Instituto de Farmacología Experimental de Córdoba; Argentin

IGF1 gene therapy in middle-aged female rats delays reproductive senescence through its effects on hypothalamic GnRH and kisspeptin neurons

The process of aging is the result of progressive loss of homeostasis and functional body impairment, including the central nervous system, where the hypothalamus plays a key role in regulating aging mechanisms. The consequences of aging include a chronic proinflammatory environment in the hypothalamus that leads to decreased secretion of gonadotropin-releasing hormone (GnRH) and impairs kisspeptin neuron functionality. In this work, we investigated the effect of insulin-like growth factor 1 (IGF1) gene therapy on hypothalamic kisspeptin/GnRH neurons and on microglial cells, that mediate the inflammatory process related with the aging process. The results show that IGF1 rats have higher kisspeptin expression in the anteroventral periventricular (AVPV) nucleus and higher immunoreactivity of GnRH in the arcuate nucleus and median eminence. In addition, IGF1-treated animals exhibit increased numbers of Iba1+ microglial cells and MHCII+/Iba1+ in the AVPV and arcuate nuclei. In conclusion, IGF1 gene therapy maintains kisspeptin production in the AVPV nucleus, induces GnRH release in the median eminence, and alters the number and reactivity of microglial cells in middle-aged female rats. We suggest that IGF1 gene therapy may have a protective effect against reproductive decline.This research was supported in part by grants #PICT13-1119 from the Argentine Agency for the Promotion of Science and Technology and grant PIP0618 from the Argentine Research Council (CONICET) to MJB, grant BFU2017-82754-R from Agencia Estatal de Investigación and CIBERFES to MAA, and grant MHE 200028 from Programa CSIC de Cooperación Científica para el Desarrollo (Programa EMHE-CSIC 2016) to MAA and MJB