Biology subjects

Boche, D.

Publications and source records attributed to Boche, D..

5 recordsLinked to original sources

bioRxiv2025

Systemic infections alter cortical transcriptional signatures in Alzheimer's disease

Alzheimers disease (AD) is characterized by neuroinflammation, yet the impact of concurrent systemic infections on the AD brain remains poorly understood. We investigated the molecular mechanisms underlying the central nervous system response to systemic infections in AD by analyzing RNA sequencing data generated in the prefrontal cortex from 202 post-mortem donors (113 AD, 89 controls), where we stratified by the presence of a respiratory infection at the time of death. We identified 763 significantly differentially expressed genes (DEGs) between AD and controls without infection, which were enriched for oxidative phosphorylation and neurodegenerative pathways. In contrast, 122 DEGs distinguished AD from controls during infection, with 57 genes uniquely altered in AD in the presence of infection, including MAPK4, VAV3, and POU3F4, implicating infection-dependent mechanisms of vascular and immune regulation. Pathway activity analysis revealed that infection in AD suppresses some immune and vascular pathways, while enhancing transcriptional and developmental programs. Weighted gene co-expression network analysis uncovered three key modules: one module strongly associated with AD, enriched for aging and signal transduction; one module linked to both AD and infection, highlighting cytoskeletal remodelling and host-pathogen interactions; and one module specific to infection, enriched in astrocytes, pericytes, and endothelial cells, implicating blood-brain barrier dysfunction. These findings suggest that systemic respiratory infections reshape transcriptional programs in the AD brain, dampening immune effector pathways and engaging vascular and host-pathogen processes in blood-brain-barrier-associated cell types. Our results highlight the complex interplay between systemic infection, neuroinflammation, and vascular responses in AD.

neuroscience↗

bioRxiv2025

Increased white matter microglial reaction and perivascular macrophages in the aging microcebe primate

As populations age, the incidence of neurodegenerative disorders is rising. Early age-related neuropathological changes are the breeding ground for the development of these disorders. Microglia are the resident macrophages of the central nervous system. They play crucial roles in maintaining brain homeostasis, yet their age-related changes remain not fully understood. While age-related microglia changes have been strongly characterized in rodents, studies in non-human primates are scarce. The microcebe primate (mouse lemur (Microcebus murinus)) is widely used as a model for cerebral aging and to investigate age-related neurodegenerative processes. HLA-DR is a major histocompatibility class II cell surface receptor which presents antigens to cells of the immune response. It is a major marker of microglia reaction. In this study, we explored microglia in the whole brains of middle-aged and old microcebes using HLA-DR immunolabeling. We analyzed microglial morphology and quantified HLA-DR+ cell density and protein expression. A wide range of microglial morphologies was observed in the white matter, including thin processes microglia, "rod-like" elongated and polarized shape, hypertrophic, and amoeboid microglia. Aging was associated with increased HLA-DR+ microglial expression in the white matter while very few HLA-DR+ microglia were observed in the parenchyma of cortical gray matter regions. A second finding was the higher number of HLA-DR+ perivascular macrophages in old animals. This study in a primate outlines that, in the absence of neurodegenerative processes, the most prominent signs of age-related microglia/macrophage changes are region-specific and concern white matter and perivascular regions. This emphasizes the need to target these regions to prevent cerebral aging. Main PointsO_LIHLA-DR+ microglia in Microcebus murinus primate show diverse morphologies and increase with age in white matter. C_LIO_LIHLA-DR+ perivascular macrophage load increase in aged animals. C_LI Table of Contents Image (TOCI) O_FIG O_LINKSMALLFIG WIDTH=167 HEIGHT=200 SRC="FIGDIR/small/645519v2_ufig1.gif" ALT="Figure 1"> View larger version (56K): org.highwire.dtl.DTLVardef@edb574org.highwire.dtl.DTLVardef@23f606org.highwire.dtl.DTLVardef@ed2e0borg.highwire.dtl.DTLVardef@169f059_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2024

Extrachromosomal DNA driven oncogene spatial heterogeneity and evolution in glioblastoma

Oncogene amplification on extrachromosomal DNA (ecDNA) is strongly associated with treatment resistance and shorter survival for patients with cancer, including patients with glioblastoma. The non-chromosomal inheritance of ecDNA during cell division is a major contributor to intratumoral genetic heterogeneity. At present, the spatial dynamics of ecDNA, and the impact on tumor evolutionary trajectories, are not well understood. Here, we investigate the spatial-temporal evolution of ecDNA and its clinical impact by analyzing tumor samples from 94 treatment-naive human IDH-wildtype glioblastoma patients. We developed a spatial-temporal computational model of ecDNA positive tumors ( SPECIES) that integrates whole-genome sequencing, multi-region DNA FISH, and nascent RNAscope, to provide unique insight into the spatial dynamics of ecDNA evolution. Random segregation in combination with positive selection of ecDNAs induce large, predictable spatial patterns of cell-to-cell ecDNA copy number variation that are highly dependent on the oncogene encoded on the circular DNA. EGFR ecDNAs often reach high mean copy number (mean of 50 copies per tumor cell), are under strong positive selection (mean selection coefficient, s > 2) and do not co-amplify other oncogenes on the same ecDNA particles. In contrast, PDGFRA ecDNAs have lower mean copy number (mean of 15 copies per cell), are under weaker positive selection and frequently co-amplify other oncogenes on the same ecDNA. Evolutionary modeling suggests that EGFR ecDNAs often accumulate prior to clonal expansion. EGFR structural variants, including vIII and c-terminal deletions are under strong positive selection, are found exclusively on ecDNA, and are intermixed with wild-type EGFR ecDNAs. Simulations show EGFRvIII ecDNA likely arises after ecDNA formation in a cell with high wild-type EGFR copy number (> 10) before the onset of the most recent clonal expansion. This remains true even in cases of co-selection and co-amplification of multiple oncogenic ecDNA species in a subset of patients. Overall, our results suggest a potential time window in which early ecDNA detection may provide an opportunity for more effective intervention. HighlightsO_LIecDNA is the most common mechanism of focal oncogene amplification in IDHwt glioblastoma. C_LIO_LIEGFR and its variants on ecDNA are particularly potent, likely arising early in tumor development, providing a strong oncogenic stimulus to drive tumorigenesis. C_LIO_LIWild-type and variant EGFR ecDNA heteroplasmy (co-occurrence) is common with EGFRvIII or c-terminal deletions being derived from EGFR wild-type ecDNA prior to the most recent clonal expansion. C_LIO_LITumors with ecDNA amplified EGFR versus PDGFRA exhibit different evolutionary trajectories. C_LIO_LISPECIES model can infer spatial evolutionary dynamics of ecDNA in cancer. C_LIO_LIA delay between ecDNA accumulation and subsequent oncogenic mutation may give a therapeutic window for early intervention. C_LI

cancer biology↗

bioRxiv2020

Study of pre-synaptic internalisation in human schizophrenia brains

AimsEfficient synaptic communication is crucial to maintain healthy behavioural and cognitive processes. Individuals affected by schizophrenia present behavioural symptoms and alterations in decision-making, suggesting altered synaptic integrity as the support of the illness. It is currently unknown how this synaptic change is mediated in schizophrenia, but microglia have been proposed to act as the culprit, actively removing synapses pathologically. Here, we aimed to explore the interaction between microglia and synaptic uptake in human post-mortem tissue. MethodsWe assessed microglial activation and synaptic internalisation by microglia in a post-mortem human tissue of 10 control and 10 schizophrenia cases. Immunohistochemistry was performed to identify microglia (Iba1 and CD68) and the presynaptic terminals (synapsin I). ResultsWe found no difference in microglial expression, nor a difference in pre-synaptic protein level phagocyted by microglia between the two groups. ConclusionsOur findings are consistent with the brain imaging studies in schizophrenia implying that microglia play a role mainly during the early phases of the disease, by example in active synapse remodelling, which is not detected in the chronic stage of the illness.

neuroscience↗

bioRxiv2019

Human tauopathies are not associated with an activated unfolded protein response

Tauopathies are the neurodegenerative diseases associated with the accumulation of misfolded tau protein. Despite many years of investigation, the mechanisms underpinning tau dependent proteinopathy remains to be elucidated. A protein quality control pathway within the endoplasmic reticulum (ER), called unfolded protein response (UPR), has been suggested as a possible response implicated in the misfolded tau-mediated neurodegeneration. However, the question arose: how does the cytosolic protein tau that does not enter the ER induce a response stemming from this compartment? In this study we investigated three different human tauopathies to establish whether these diseases are associated with the activation of UPR. We probed for the modulation of several reliable UPR markers in mRNA and proteins extracted from 20 brain samples from Alzheimers disease (AD) patients, 11 from Picks disease (PiD) and 10 from Progressive Supranuclear Palsy (PSP) patients coupled to equal numbers of age-matched non-demented controls. This showed that different markers of UPR are not changed in any of the human tauopathies investigated. Interestingly, UPR signatures were often observed in non-demented controls. These data from human tissue further support the emerging evidence that the accumulation of misfolded cytosolic tau does not drive a diseased associated activation of UPR.

neuroscience↗