Biology subjects

Ribeiro, F. M.

Publications and source records attributed to Ribeiro, F. M..

3 recordsLinked to original sources

bioRxiv2019

Gender-specific pathophysiological mGluR5-dependent Aβ oligomer signaling in Alzheimer mice

Sex is a key modifier of the prevalence and progression of Alzheimers disease (AD). {beta}- Amyloid (A{beta}) deposition is a pathological hallmark of AD and aberrant activation of metabotropic glutamate receptor 5 (mGluR5) by A{beta} has been linked to AD progression. We find that mGluR5 exhibits distinct sex-dependent pharmacological profiles. Specifically, endogenous mGluR5 from male mouse cortex and hippocampus binds with high-affinity to A{beta} oligomers whereas, female mGluR5 exhibits no affinity to A{beta} oligomers. The binding affinity of mGluR5 to A{beta} oligomer is dependent on its interaction with cellular prion protein (PrPC) as mGluR5 co-immunoprecipitates with PrPC from male, but not female, mouse brain. A{beta} oligomers also bind with high-affinity to human mGluR5 in male, but not female, cortex. The mGluR5/A{beta} oligomer/PrPC ternary complex is essential to elicit mGluR5-dependent pathological signaling and as a consequence mGluR5-regulated GSK3{beta}/ZBTB16 autophagic signaling is dysregulated in male, but not female, primary neuronal cultures. These sex-specific differences in mGluR5 signaling translate into in vivo differences in mGluR5-dependent pathological signaling between male and female AD mice. We show that the chronic inhibition of mGluR5 using a mGluR5-selective negative allosteric modulator reactivates GSK3{beta}/ZBTB16-regulated autophagy, mitigates A{beta} pathology and reverses cognitive decline in male, but not female, APPswe/PS1{Delta}E9 mice. Thus, it is evident that, unlike male brain, mGluR5 does not contribute to A{beta} pathology in female AD mice. This study highlights the complexity of mGluR5 pharmacology and A{beta} oligomer-activated pathological signaling and emphasizes the need for clinical trials redesign and analysis of sex-tailored treatment for AD.

neuroscience↗

bioRxiv2019

Short and long TNF-alpha exposure recapitulates canonical astrogliosis events in human induced pluripotent stem cells-derived astrocytes

Astrogliosis comprises a variety of changes in astrocytes that occur in a context-specific manner, triggered by temporally diverse signaling events that vary with the nature and severity of brain insults. However, most mechanisms underlying astrogliosis were described using animal models, which fail to reproduce some aspects of human astroglial signaling. Here, we report an in vitro model to study astrogliosis using human induced pluripotent stem cells (iPSC)-derived astrocytes which replicates aspects temporally intertwined of reactive astrocytes in vivo. We analyzed the time course of astrogliosis by measuring nuclear translocation of NF-kB, secretion of cytokines and changes in morphological phenotypes of human iPSC-derived astrocytes exposed to TNF-. It was observed the NF-kB nuclear translocation, increases either in the inflammation-related cytokines secretion and gene expression for IL-1{beta}, IL-6 and TNF- following 24 h TNF- stimulation. After 5 days, human iPSC-derived astrocytes exposed to TNF- exhibited increases in vimentin and GFAP immunolabeling, elongated shape and shrinkage of nuclei, which is typical phenotypes of astrogliosis. Moreover, about a 50% decrease in D-[3H] aspartate uptake was observed over the astrogliosis course with no evident cell damage, which suggests astrocytic dysfunction. Taken together, our results indicate that cultured human iPSC-derived astrocytes reproduce canonical events associated to astrogliosis in a time dependent fashion. Our findings may contribute to a better understanding of mechanisms governing human astrogliosis. Furthermore, the approach described here presents a potential applicability as a platform to uncover novel biomarkers and new drug targets to refrain astrogliosis associated to human brain disorders.

neuroscience↗

bioRxiv2019

The response of genes and pathways of immunological system induced by irradiation

Current studies have shown that ionizing radiation (IR) could increase the efficiency of radiation therapy by the stimulation of the immune system. This occurs in low-dose radiation as well as doses within hypofractionated range usually used in radiotherapy. However, the elucidation of the mechanisms of immunogenic modulation reported at these doses remain an issue. In this study, we analyzed transcriptome data available in Gene Expression Omnibus (GEO) database related to B cells isolated from whole blood of 95 donors and then irradiated with 10 Gy. The aim of this study is to investigate the regulation of genes and pathways of the immune system considering the B7-CD28/CTLA4 superfamily, CD40-CD40LG molecules, and cytokines expressed by B cells irradiated. The connection between genes and pathways is established by the Reactome database. Relative activity and diversity of pathways were calculated to determine the modulation of the immune system response to irradiation. Analysis of variance (ANOVA) with repeated measures and Bonferronis method were used to determine differentially expressed genes. It was observed that IR up-modulates the response of pathways and genes considered in this study, which indicates that 10 Gy can enhance antitumor immune responses.

biophysics↗