Biology subjects

Brunialti, E.

Publications and source records attributed to Brunialti, E..

6 recordsLinked to original sources

bioRxiv2026

Do nanoplastics reshape microglial support of neuronal resilience? A study of microglial bioenergetics and microglia to neuron communication in vitro

Nanoplastics (NPs) are emerging environmental contaminants able to cross biological barriers, disrupt cellular and organelle homeostasis, and alter the brain microenvironment. This study investigated whether NPs affect microglia-neuron communication, a key mechanism underlying neuronal resilience, via the nuclear factor erythroid 2-like 2 (NFE2L2) pathway. Using an in vitro model, we evaluated the effects of polystyrene nanoplastics on microglial metabolic fitness and microglia-mediated neuronal stress responses. Increasing NP concentrations induced a dose-dependent biphasic effect. Low to intermediate concentrations increased intracellular adenosine triphosphate (ATP) levels in microglia and enhanced microglia-mediated activation of neuronal NFE2L2. In contrast, high NP concentration impaired microglial metabolism, reduced ATP availability, and decreased microglia-neuron communication. These findings indicate that NPs alter microglial energetic status and modulate neuroprotective signalling, potentially contributing to impaired neuron-microglia interactions and increased susceptibility to neurotoxicity. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=129 SRC="FIGDIR/small/732827v1_ufig1.gif" ALT="Figure 1"> View larger version (69K): org.highwire.dtl.DTLVardef@d33f79org.highwire.dtl.DTLVardef@ec4542org.highwire.dtl.DTLVardef@1b71ca3org.highwire.dtl.DTLVardef@b92ad4_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LINanoplastics alter microglial metabolic fitness in vitro. C_LIO_LINanoplastics biphasically modulate microglial support of neurons. C_LIO_LIHigh nanoplastic concentration reduces microglial support to neurons. C_LIO_LIMicroglial bioenergetics may link nanoplastics to neuronal vulnerability. C_LI

pharmacology and toxicology↗

bioRxiv2026

Identification of ICAM-1-targeting DNA aptamers as a host-directed strategy to inhibit Human Rhinovirus infection

Exacerbations of respiratory viral infections significantly contribute to morbidity and healthcare burden. Among these viruses, Human Rhinoviruses (HRVs) are the most frequent causative agents of upper respiratory tract infections. To date, over 150 HRV serotypes have been identified, classified into three species: HRV-A, HRV-B, and HRV-C. No antiviral therapies are currently available against this viral family, largely due to the high serotype diversity and limited cross-protection. The major group of HRVs relies on the Intercellular Adhesion Molecule-1 (ICAM-1) receptor to infect airway epithelial cells, making ICAM-1 an attractive target for broad-spectrum therapeutic interventions. Here, we report the development of nucleic acid-based aptamers designed to disrupt ICAM-1-HRV binding and thereby prevent viral infection. Aptamers are single-stranded DNA molecules that fold into precise three-dimensional structures, enabling highly specific protein recognition. Using a Systematic Evolution of Ligands by EXponential Enrichment (SELEX) approach guided by a minimal peptide mimicking the ICAM-1 viral binding interface, a library of >1024 random single-stranded DNA sequences was screened. Through iterative rounds of selection, we identified eight candidate 77-nt DNA aptamers, which were subsequently evaluated for their potential using in silico and in vitro assays, as well as functional assays in human epithelial cells. From this strategy, two lead aptamers were selected that effectively inhibited HRV-A16 replication in a concentration-dependent manner, as measured by viral titers (TCID assay) and viral RNA quantification by RT-PCR. These findings demonstrate the potential of ICAM-1-targeting aptamers as antiviral agents capable of preventing HRV entry. By targeting a host receptor and creating a protective barrier at the cell surface, this approach may offer a broadly applicable strategy against multiple HRV serotypes, paving the way for the development of novel antiviral interventions. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=131 SRC="FIGDIR/small/717810v1_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@130d8org.highwire.dtl.DTLVardef@2dd09borg.highwire.dtl.DTLVardef@1da744eorg.highwire.dtl.DTLVardef@109ea5b_HPS_FORMAT_FIGEXP M_FIG C_FIG

pharmacology and toxicology↗

bioRxiv2026

Spatiotemporal atlas of pro-inflammatory (NF-kB) and anti-inflammatory (STAT6) signalling using reporter mice during mRNA vaccination

The immunization process unfolds through a precisely orchestrated sequence of innate and adaptive events across distinct anatomical sites. Although many mechanisms underlying vaccination are well described, most vaccines have been developed empirically, partly due to the lack of tools enabling rapid, organ-specific analysis of immune activation. To address this gap, we developed and validated a novel STAT6 reporter mouse enabling dynamic in vivo whole-body imaging and ex vivo analysis of STAT6-mediated anti-inflammatory signalling, and combined it with an established NF-{kappa}B reporter model to dissect immune activation induced by two LNP-encapsulated mRNA vaccines encoding the same antigen but differing in RNA chemistry (unmodified versus N{superscript 1}-methyl-pseudouridine (m{superscript 1}{Psi})-modified). This dual-reporter system enabled the creation of a spatiotemporal atlas of vaccine-induced signalling, revealing chemistry-dependent immune dynamics and identifying the liver as a predominant early hub for both NF-{kappa}B and STAT6 activity following systemic administration. Integration with antibody measurements demonstrated that early STAT6 activation followed by rapid signal resolution--rather than prolonged NF-{kappa}B-mediated inflammation--correlated with robust humoral responses, suggesting that monitoring NF-{kappa}B and STAT6 dynamics could provide predictive insight into vaccine immunogenicity. Together, these findings establish NF-{kappa}B and STAT6 reporter mice as rapid in vivo screening tools for the early assessment of vaccine immunogenicity and performance. By enabling dynamic, organ-resolved immune profiling, this approach paves the way for more rational, mechanism-driven design of mRNA vaccines and underscores the importance of further investigating the effects of vaccines on the liver, both as a primary LNP target and as an immunologically tolerogenic organ.

immunology↗

bioRxiv2025

Metabolic reprogramming and altered ATP content impair neuroprotective functions of microglia in β-glucocerebrosidase deficiency models

Mutations in the GBA gene, which reduce {beta}-glucocerebrosidase (GCase) activity, represent the most significant genetic risk factor for Parkinsons disease (PD). Decreased GCase activity has also been observed in sporadic PD cases, supporting a broader role for GCase in the poorly understood mechanisms underlying PD etiopathogenesis. While most studies on the relationship between GBA mutations and PD have focused on neurons, evidence suggests that PD pathology promoted by GCase deficiency involves other cell types and, in particular, interactions between neuronal and glial cells. Here, we identify microglia as primary players undergoing significant alterations at early stages of the pathological processes triggered by a GCase impairment. Using both pharmacological and genetic mouse models of GCase deficiency, we observed microglial morphological, transcriptional and metabolic changes. Interestingly, these changes were associated with a cell-specific, significant reduction of microglial ATP levels. When microglial ATP depletion was reproduced in an in vitro system of co-cultured microglial and neuronal cells, the neuroprotective properties of microglia were compromised and neuronal susceptibility to oxidative stress was enhanced. These findings underscore the role of microglia in PD pathogenesis and point to a pathogenetic mechanism by which microglial metabolic disturbances leading to ATP depletion enhance neuronal vulnerability to injury and neurodegeneration. This mechanism could be targeted for therapeutic intervention aimed at mitigating PD risk and counteracting the development of PD pathology. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=112 SRC="FIGDIR/small/656111v2_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@dfd3d7org.highwire.dtl.DTLVardef@ccf2c2org.highwire.dtl.DTLVardef@155d241org.highwire.dtl.DTLVardef@15ed00a_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2022

Sex-specific microglial responses to glucocerebrosidase inhibition: relevance to GBA1-linked Parkinson disease

Microglia are heterogenous cells characterized by distinct populations each contributing to specific biological processes in the nervous system, including neuroprotection. To elucidate the impact of sex-specific microglia heterogenicity to the susceptibility of neuronal stress, we analysed the dynamic changes in shape and motility occurring in primary mouse microglia following pro-inflammatory or neurotoxic insults, thus finding sex-specific responses of microglial subpopulations. Male microglia exhibited a pro-inflammatory phenotype, whereas female microglia showed enhanced neuroprotective capabilities associated with the activation of Nrf2 detoxification pathway in neurons. The sex difference in neuroprotective functions is lost by inhibition of glucocerebrosidase, the product of the GBA1 gene, mutations of which are the major risk factor for Parkinsons disease (PD). This finding is consistent with the increased risk of PD observed in female carriers of GBA1 mutation, when compared with wild type population, suggesting a role for microglial functionality in the etiopathogenesis of PD-GBA1.

neuroscience↗

bioRxiv2021

Inhibition of microglial GBA hampers the microglia-mediated anti-oxidant and protective response in neurons

Homozygotic mutations in the GBA gene cause Gauchers disease, moreover, both patients and heterozygotic carriers have been associated with 20- to 30-fold increased risk of developing Parkinsons disease. In homozygosis, these mutations impair the activity of {beta}-glucocerebrosidase, the enzyme encoded by GBA, and generate a lysosomal disorder in macrophages, which changes morphology towards an engorged phenotype, considered the hallmark of Gauchers disease. In the brain, most of the pathological effects caused by GBA mutations have been attributed to the {beta}-glucocerebrosidase deficit in neurons, while a microglial phenotype for these mutations has never been reported. Here, we applied the bioluminescence imaging technology, immunohistochemical and gene expression analysis to investigate the consequences of microglial {beta}-glucocerebrosidase inhibition in the brain of reporter mice, in primary neuron/microglia co-cultures and in cell lines. Our data demonstrate the existence of a novel mechanism by which microglia sustain the antioxidant/detoxifying response mediated by the nuclear factor erythroid 2-related factor 2 in neurons. The central role played by microglia in this neuronal response in vivo was proven by pharmacological depletion of the lineage in the brain, while co-cultures experiments provided insight on the nature of this cell-to-cell communication showing that this mechanism requires a direct microglia-to-neuron contact supported by functional actin structures. Pharmacological inhibition of microglial {beta}-glucocerebrosidase was proven to induce morphological changes, turn on an anti-inflammatory/repairing pathway and hinder the microglia ability to activate the anti-oxidant/detoxifying response, thus increasing the neuronal susceptibility to neurotoxins. Altogether, our data suggest that microglial {beta}-glucocerebrosidase inhibition impairs microglia-to-neuron communication increasing the sensitivity of neurons to oxidative or toxic insults, thus providing a possible mechanism for the increased risk of neurodegeneration observed in carriers of GBA mutations. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=154 SRC="FIGDIR/small/427380v1_ufig1.gif" ALT="Figure 1"> View larger version (60K): org.highwire.dtl.DTLVardef@15c2c3corg.highwire.dtl.DTLVardef@5c4e34org.highwire.dtl.DTLVardef@12718dorg.highwire.dtl.DTLVardef@dcfeca_HPS_FORMAT_FIGEXP M_FIG C_FIG In BriefMicroglia, through actin-dependent structures, contact neurons and induce a detoxification response by increasing the NFE2L2 signalling pathway. Inhibition of GCase activity by CBE treatment produces a morpho-functional change in microglia cells hampering the neuroprotective microglia-neuron communication thus inducing a phenotype in dopaminergic neurons characterized by increased susceptibility to oxidative stress or toxic insults.

neuroscience↗