Biology subjects

Verheijen, M.

Publications and source records attributed to Verheijen, M..

9 recordsLinked to original sources

bioRxiv2026

Temporal effects of a single oral dose of psilocybin on plasma circulating miRNAs in healthy young adults.

BackgroundPsilocybin, a classic psychedelic, produces acute alterations in brain function, and has shown sustained therapeutic effects in psychiatric disorders. However, most studies focus on acute brain imaging readouts (e.g., fMRI) and rarely assess longer-term molecular changes. MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression, are enriched in the brain, and can be released into blood, potentially indexing brain-relevant molecular processes. We hypothesised that a single psilocybin dose would show acute changes in miRNAs with predicted relevance to neuroplasticity related signalling and immune/inflammatory regulation in healthy adults. MethodsIn a randomised, double-blind, placebo-controlled study (N=62; 31 psilocybin, 31 placebo), volunteers received psilocybin (0.17 mg/kg) or placebo. Blood was collected at baseline, 360 minutes, and 7 days after dosing. Plasma miRNAs were quantified by small RNA sequencing. Elastic net regression was used for feature selection, followed by differential expression analysis and validation with linear mixed models. Pathway enrichment used Reactome and Gene Ontology. ResultsTwo circulating miRNAs (let-7g-5p and miR-150-5p) met criteria for differentially expressed at 360 minutes following psilocybin administration, with no significant differences detected at 7 days or in the placebo condition under the statistical thresholds used. Over representation analysis suggested enrichment of molecular processes involved in neuroplasticity (e.g., TrkA, MAPK), inflammation (e.g., IL-6, TGF-{beta}), and transcriptional regulation (e.g., RNA polymerase II, SMAD2/3/4). ConclusionsA single oral dose of psilocybin was associated with transient alterations in circulating miRNA expression, consistent with an acute shift in circulating gene-regulatory miRNA signals, without sustained miRNA changes at 7 days. These findings provide initial evidence that circulating miRNA changes after psilocybin may reflect acute molecular process responses and support further investigation of circulating miRNAs as potential biomarkers of psychedelic-induced molecular responses.

neuroscience↗

bioRxiv2026

Circulating MicroRNAs and Their Associations with Neurotrophic, Inflammatory and Glutamate Markers in Healthy Volunteers

Psilocybin acutely alters neurotrophic, neurochemical, and immune markers, but the relationships between these responses and circulating microRNAs (miRNAs), i.e. non-coding RNAs that regulate post-transcriptional gene expression, remain unclear. In a randomized, double-blind, placebo-controlled study of 62 healthy adults who received psilocybin (0.17 mg/kg) or placebo, we previously demonstrated that let-7g-5p and miR-150-5p were transiently differentially expressed 360 minutes after psilocybin administration. Here, we examined whether changes in these miRNAs were associated with concurrent neurotrophic, inflammatory, pharmacokinetic, and glutamatergic measures. Expression changes from baseline to 360 min and 7 days were analysed using linear regression against changes in BDNF, TNF-, IL-6, C-reactive protein, cortisol, medial prefrontal cortex glutamate/total creatine, and psilocin concentrations. Psilocybin increased let-7g-5p and decreased miR-150-5p expression. Changes in let-7g-5p were positively associated with psilocin concentrations, suggesting sensitivity to inter-individual pharmacokinetic variability, whereas miR-150-5p showed no concentration-dependent association. In both groups, miRNA changes were negatively related to baseline expression: lower baseline let-7g-5p predicted larger increases, whereas higher baseline miR-150-5p predicted larger decreases. BDNF changes were associated with both miRNAs under placebo but not psilocybin, consistent with reduced between-subject variability and a flattened BDNF-miRNA relationship following treatment. Medial prefrontal glutamate was negatively associated with miR-150-5p change under psilocybin. No associations were found with immune biomarkers. Together, these findings support the predicted involvement of let-7g-5p and miR-150-5p in neuroplasticity and their potential as accessible blood-based biomarkers of individual neurobiological responsiveness to psilocybin and other psychedelics.

neuroscience↗

bioRxiv2026

Quorum sensing underlies the establishment and maintenance of marginal zone B cells

The marginal zone (MZ) of the spleen harbors B cells that play an indispensable role in immune defense, orchestrating rapid responses to bloodborne pathogens. Under steady-state conditions, MZ B cell numbers are maintained through the balance of de novo generation from precursors, proliferative self-renewal, and loss. The mechanisms governing this homeostatic control remain elusive. Further, the developmental pathways underlying the establishment and continued supplementation of the MZ B cell compartment are not fullyelucidated. To address these gaps, we combined multiple fate-mapping tools and mathematical models to study MZ B cell dynamics in mice across the life course. Our analyses find evidence of quorum sensing mechanisms that regulate both the accumulation of mature MZ B cells during early life and their maintenance throughout adulthood. Specifically, we demonstrate that they derive predominantly from transitional B cell precursors with an efficiency that increases with age, reaching stable levels only in adulthood. MZ B cells compensate for this early developmental inefficiency through cell density-dependent proliferation, ensuring the timely establishment of a stable pool. Collectively, these findings unveil critical roles of quorum sensing and immune system maturation in the maintenance of this vital B cell subset.

immunology↗

bioRxiv2026

Deletion of astrocyte intermediate filaments GFAP and Vimentin enhances protein synthesis and prevents early synaptic and cognitive dysfunction in a mouse model of Alzheimer's disease

In Alzheimers disease (AD) astrocytes become reactive, displaying hypertrophic morphology, increased expression of intermediate filament proteins GFAP and Vimentin and impaired homeostatic support to neurons. However, the contribution of reactive astrocytes to AD progression, particularly the role of cytoskeletal hypertrophy, remains unclear. Here, we investigate whether astrocyte intermediate filaments actively contribute to early AD progression. We show that astrogliosis appears as early as at 3 months in APP/PS1 mice, preceding amyloid-{beta} plaque deposition, and is characterized by a strong upregulation of GFAP and Vimentin. Genetic ablation of GFAP and Vimentin attenuated astrogliosis, as evidenced by the absence of hypertrophy of astrocyte processes and restored expression of glutamine synthetase and other proteins altered in reactive astrocytes in AD. Importantly, GFAP and Vimentin deletion prevented cognitive decline in 4-month old male and female mice, independently of amyloid plaque pathology or microglial reactivity. Mass-spectrometry based proteomics of the dorsal hippocampus revealed a downregulation of synaptic proteins and dysregulation of ribosomal and RNA-binding proteins in APP/PS1 mice, both of which were rescued by GFAP and Vimentin deletion. Using astrocyte-specific CRISPR-Cas9-mediated knockout of GFAP and Vimentin, we further demonstrate translation impairments in AD astrocytes, and that GFAP and Vimentin deletion restores this impaired astrocytic translation. Together, our findings identify intermediate filament proteins GFAP and Vimentin as active regulators of astrocyte protein synthesis, and reveal a previously unrecognized mechanism by which reactive astrocytes contribute to early cognitive dysfunction in AD. This highlights these astrocyte intermediate filaments as promising therapeutic targets to counteract reactive astrocyte-driven cognitive decline in the early stages of Alzheimers disease.

neuroscience↗

bioRxiv2023

Early-life stress exposure impacts the hippocampal synaptic proteome in a mouse model of Alzheimer's disease: age- and pathology-dependent effects on mitochondrial proteins

Epidemiological evidence indicates that early life stress (ES) exposure increases the risk for later-life diseases, such as Alzheimers disease (AD). Accordingly, we and others have shown that ES aggravates the development of, and response to, amyloid-beta (A{beta}) pathology in animal models. Moreover, ES-exposed transgenic APP/PS1 mice display deficits in both cognitive flexibility and synaptic function. As the mechanisms behind these changes were unclear, we here investigated how exposure to ES, using the limited nesting and bedding model, affects the synaptic proteome across 2 different ages in both wildtype and APP/PS1 transgenic mice. We found that, compared to wildtype mice, the hippocampal synaptosomes of APP/PS1 mice at an early pathological stage (4 months) showed a higher abundance of mitochondrial proteins and lower levels of proteins involved in actin dynamics. Interestingly, ES exposure in wildtype mice had similar effects on the level of mitochondrial and actin-related synaptosomal proteins at this age, whereas ES exposure had no additional effect on the synaptosomal proteome of early-stage APP/PS1 mice. Accordingly, ultrastructural analysis of the synapse using electron microscopy in a follow-up cohort showed fewer mitochondria in pre- and post-synaptic compartments of APP/PS1 and ES-exposed mice, respectively. At a later pathological stage (10 months), the hippocampal synaptic proteome of APP/PS1 mice revealed an upregulation of proteins related to A{beta} processing, that was accompanied by a downregulation of proteins related to postsynaptic receptor endocytosis. ES exposure no longer affected the synaptic proteome of wildtype animals by this age, whereas it affected the expression of astrocytic proteins involved in lipid metabolism in APP/PS1 mice. We confirmed a dysregulation of astrocyte protein expression in a separate cohort of 12-month-old mice, by immunostaining for the alpha subunit of the mitochondrial trifunctional protein and fatty acid synthase in astrocytes. In conclusion, our data suggest that ES and amyloidosis share pathogenic pathways involving synaptic mitochondrial dysfunction and astrocytic lipid metabolism. These pathways might be underlying contributors to the long-term aggravation of the APP/PS1 phenotype by ES, as well as to the ES-associated risk for AD progression. These data are publicly accessible online as a web app via https://amsterdamstudygroup.shinyapps.io/ES_Synaptosome_Proteomics_Visualizer/.

neuroscience↗

bioRxiv2022

The fidelity of transcription in human cells

Accurate transcription is required for the faithful expression of genetic information. To provide insight into the molecular mechanisms that control the fidelity of transcription, we analyzed the landscape of transcription errors in human embryonic stem cells. These measurements provide the first reasonable estimate of the fidelity of transcription in human cells and identify multiple genetic and epigenetic factors that control its accuracy. In addition, we developed a new reporter mouse to identify cell types and tissues that commit these errors the most. These experiments revealed that CA1 and dentate gyrus neurons are highly sensitive to transcriptional mutagenesis, lending new support to the hypothesis that transcription errors play a role in the progression of Alzheimers disease. Taken together, these experiments provide unprecedented insight into the fidelity of gene expression in human cells and the molecular mechanisms that govern the central dogma of life.

genetics↗

bioRxiv2022

Proximity of astrocyte leaflets to the synapse determines memory strength

SummaryAstrocyte distal processes, known as leaflets or perisynaptic astrocyte processes (PAPs), fine-tune synaptic activity by clearing neurotransmitters and limiting extrasynaptic glutamate diffusion. While learning and memory depends on orchestrated synaptic activity of neuronal ensembles within the hippocampus, it is becoming increasingly evident that astrocytes residing in the environment of these synapses play a central role in shaping memories. However, how astroglial synaptic coverage contributes to mnemonic processing remains largely unknown. Here, we targeted astrocyte leaflet structure in vivo by depleting Ezrin, an integral leaflet-structural protein, in astrocytes of the adult hippocampal CA1 using a CRISPR-Cas9 genetic approach. This resulted in significantly smaller astrocyte territories and reduced astroglial synaptic coverage. In addition, using genetically encoded glutamate sensors and whole-cell patch-clamp recordings from pyramidal neurons, we found that Ezrin deletion and the resultant manipulation of leaflet structure boosted extrasynaptic glutamate diffusion and NMDA-receptor activation. Importantly, these cellular phenotypes translated to enhanced fear memory expression that was accompanied by increased activation of CA1 pyramidal neurons in the days after learning occurred. We show that Ezrin is critical for astrocyte morphology as well as for adult hippocampal synapse integrity and function. Our data show that astrocyte leaflet structure gates memory strength by regulating glutamate spillover in the vicinity of memory-related synaptic activity.

neuroscience↗

bioRxiv2019

Fate mapping quantifies the dynamics of B cell development and activation throughout life

Follicular mature (FM) and germinal centre (GC) B cells underpin humoral immunity but the dynamics of their generation and maintenance are not clearly defined. Here we exploited a fate-mapping system in mice that tracks B cells as they develop into peripheral subsets, together with a cell division fate reporter mouse and mathematical models. We find that FM cells are kinetically homogeneous, recirculate freely, continually replenished from transitional populations, and self-renew rarely. In contrast, GC B cell lineages persist for weeks with rapid turnover and site-specific dynamics. Those in the spleen derive from transitional cells and are kinetically homogeneous, while those in lymph nodes derive from FM B cells and comprise both transient and persistent clones. These differences likely derive from the nature of antigen exposure at the different sites. Our integrative approach also reveals how the host environment drives cell-extrinsic, age-related changes in B cell homeostasis.

immunology↗

bioRxiv2018

Integrated Stress Response Deregulation underlies Vanishing White Matter and is a target for therapy

Vanishing white matter (VWM) is a fatal, stress-sensitive leukodystrophy that mainly affects children and is currently without treatment. VWM is caused by recessive mutations in eukaryotic initiation factor 2B (eIF2B) that is crucial for initiation of mRNA translation and its regulation under stress conditions. Mice with bi-allelic missense mutations in eIF2B recapitulate human VWM. VWM pathomechanisms are unclear. Using polysomal profiling to screen for mRNAs with altered translation we observed most prominent changes in expression of integrated stress response (ISR) mRNAs in brains of mutant compared to wild-type mice; expression levels correlated with disease severity. We substantiated these findings in VWM patients brains. ISRIB, an ISR inhibitor, normalized expression of mRNA markers, ameliorated white matter pathology and improved motor skills in VWM mice, thus showing that the ISR is central in VWM pathomechanisms and a viable target for therapy.\n\nOne Sentence SummaryISRIB ameliorates ISR deregulation and clinical signs in VWM mice

neuroscience↗