Biology subjects

Brouwer, N.

Publications and source records attributed to Brouwer, N..

7 recordsLinked to original sources

bioRxiv2025

Drug Response Prediction Provides a Biologically Relevant Benchmark for Perturbation Response Models

Perturbation response models (PRMs) predict transcriptional responses to interventions such as gene knockout or drug treatments. While simple baseline models match PRMs in reconstructing post-treatment profiles, we show that drug response predictors trained on PRM-generated profiles significantly outperform those trained on baseline or pre-treatment profiles. Unlike simple baseline models, PRMs preserve variation in response-relevant genes, making them a highly valuable tool for predicting drug response.

bioinformatics↗

bioRxiv2023

Radiotherapy induces persistent innate immune reprogramming of microglia into a primed state

More than half of all brain tumour survivors experience debilitating and often progressive cognitive decline after treatment with radiotherapy. Microglia, the resident macrophages in the brain, have been implicated in this decline. In response to various insults microglia can develop innate immune memory (IIM), which can either enhance (priming) or repress (tolerance) the response to subsequent inflammatory challenges. Here, we investigated whether radiation affects the IIM of microglia by irradiating the brains of rats and later exposing them to a secondary inflammatory stimulus. Comparative transcriptomic profiling and protein validation of microglia isolated from irradiated rats showed a stronger immune response to a secondary inflammatory insult demonstrating that radiation can lead to long-lasting molecular reprogramming of microglia. Transcriptomic analysis of post-mortem normal-appearing non-tumour brain tissue of glioblastoma patients indicates that radiation-induced microglial priming is conserved in humans. Targeting microglial priming after radiotherapy or avoiding further inflammatory insults could decrease radiotherapy-induced neurotoxicity.

neuroscience↗

bioRxiv2022

Early-life stress lastingly impacts microglial transcriptome and function under basal and immune-challenged conditions

Early-life stress (ELS) leads to increased vulnerability to psychiatric disorders including depression later in life. Neuroinflammatory processes have been implicated in ELS-induced negative health outcomes, but how ELS impacts microglia, the main tissue-resident macrophages of the central nervous system, is unknown. Here, we determined the effects of ELS induced by limited bedding and nesting material during the first week of life (postnatal days [P]2 - 9) on microglial i) morphology; ii) hippocampal gene expression; and iii) synaptosome phagocytic capacity in male pups (P9) and adult (P200) mice. The hippocampus of ELS-exposed adult mice displayed altered proportions of morphological subtypes of microglia, as well as microglial transcriptomic changes related to the tumor necrosis factor response and protein ubiquitination. ELS exposure leads to distinct gene expression profiles during microglial development from P9 to P200 and in response to an LPS challenge at P200. Functionally, synaptosomes from ELS-exposed mice were phagocytosed less by age-matched microglia. At P200, but not P9, ELS microglia showed reduced synaptosome phagocytic capacity when compared to CTRL microglia. Lastly, we confirmed the ELS-induced increased expression of the phagocytosis-related gene GAS6 that we observed in mice, in the dentate gyrus of individuals with a history of child abuse using in situ hybridization. These findings reveal persistent effects of ELS on microglial function and suggest that altered microglial phagocytic capacity is a key contributor to ELS-induced phenotypes.

neuroscience↗

bioRxiv2021

Brain macrophages acquire distinct transcriptomes prior to demyelination in multiple sclerosis

Multiple sclerosis (MS) is a disease of the central nervous system (CNS) that is characterized by inflammation and focal areas of demyelination, ultimately resulting in axonal degradation and neuronal loss. Several lines of evidence point towards a role for microglia and other brain macrophages in disease initiation and progression, but exactly how lesion formation is triggered is currently unknown. Here, we characterized early changes in MS brain tissue through transcriptomic analysis of normal appearing white matter (NAWM). We found that NAWM was characterized by enriched expression of genes associated with inflammation and cellular stress derived from brain macrophages. Single cell RNA sequencing confirmed an early stress response in brain macrophages in NAWM and identified specific macrophage subsets that associate with different stages of demyelinating lesions. These early changes associated with lesion development in MS brain tissue may provide therapeutic targets to limit lesion progression and demyelination.

neuroscience↗

bioRxiv2021

Epigenetic regulation of innate immune memory in microglia

Microglia are the tissue-resident macrophages of the CNS. They originate in the yolk sac, colonize the CNS during embryonic development and form a self-sustaining population with limited turnover. A consequence of their relative slow turnover is that microglia can serve as a long-term memory for inflammatory or neurodegenerative events. We characterized the epigenomes and transcriptomes of microglia exposed to different stimuli; an endotoxin challenge (LPS) and genotoxic stress (DNA repair deficiency-induced accelerated aging). Whereas the enrichment of permissive epigenetic marks at enhancer regions explains training (hyperresponsiveness) of primed microglia to LPS challenge, the tolerized response of microglia seems to be regulated by loss of permissive epigenetic marks. Here, we identify that inflammatory stimuli and accelerated aging because of genotoxic stress activate distinct gene networks. These gene networks and associated biological processes are partially overlapping, which is likely driven by specific transcription factor networks, resulting in altered epigenetic signatures and distinct functional (desensitized vs. primed) microglia phenotypes.

neuroscience↗

bioRxiv2020

Distinct gene expression profiles in leukocortical demyelinated white and grey matter areas of Multiple Sclerosis patients

Demyelination of the CNS is a prominent pathological hallmark of Multiple Sclerosis (MS) and affects both white (WM) and grey matter (GM). However, demyelinated WM and GM areas exhibit clear pathological differences, most notably the presence or absence of inflammation and activated glial cells in WM and GM, respectively. In order to gain more insight into the differential pathology of demyelinated WM and GM areas, we micro-dissected neighbouring WM and GM demyelinated areas as well as normal appearing matter from leukocortical lesions of human post-mortem material and used these samples for RNA-sequencing. Our data show that even neighbouring WM and GM demyelinated areas share only 10% overlap in gene expression, implying a distinct gene expression profile, which is extending to a specific glial cell related signature. We propose that, based on their distinct expression profile, pathological processes in neighbouring WM and GM are likely different which could have implications for the efficacy of current MS treatments.

neuroscience↗

bioRxiv2020

Profiling microglia from AD donors and non-demented elderly in acute human post-mortem cortical tissue

Microglia are the tissue-resident macrophages of the central nervous system (CNS). Recent studies based on bulk and single-cell RNA sequencing in mice indicate high relevance of microglia with respect to risk genes and neuro-inflammation in Alzheimers disease. Here, we investigated microglia transcriptomes at bulk and single cell level in non-demented elderly and AD donors using acute human post-mortem cortical brain samples. We identified 9 human microglial subpopulations with heterogeneity in gene expression. Notably, gene expression profiles and subcluster composition of microglia did not differ between AD donors and non-demented elderly in bulk RNA sequencing nor in single-cell sequencing.

neuroscience↗