Biology subjects

van den Hove, D.

Publications and source records attributed to van den Hove, D..

8 recordsLinked to original sources

bioRxiv2026

Disrupted myelin homeostasis in grey matter of Alzheimer's disease

Alzheimers disease (AD) is characterized not only by amyloid-{beta} plaques, tau neurofibrillary tangles and associated neuronal loss, but also by alterations in non-neuronal cell types essential for neuronal support. Oligodendrocytes and their myelin sheaths play a central role in maintaining axonal function, yet detailed molecular profiling of myelin dynamics in the human AD brain remains limited. Although neuroimaging studies increasingly highlight myelin degeneration in white matter as an important contributor to AD pathophysiology, the status of myelin within cortical grey matter is less well understood. Here, we performed a detailed histopathological characterization of myelin integrity and oligodendrocyte dynamics in both grey and white matter of the middle temporal gyrus (MTG), making use of post-mortem tissue from AD cases (n = 15) and age-, sex-, and APOE genotype-matched controls (n = 15). Strikingly, we identified a specific vulnerability of cortical grey matter myelin in AD, whereas white matter myelin appeared relatively preserved. This selective grey matter disruption was accompanied by a seemingly insufficient oligodendrocyte regenerative response, suggesting ongoing attempts at myelin repair, yet featured by a differentiation block. Importantly, the extent of myelin damage and OPC differentiation strongly correlated with proximity to tau pathology, linking cortical demyelination to neuronal and synaptic dysfunction within vulnerable AD regions. Together, our findings reveal cortical grey matter myelin disruption as a previously underrecognized, highly localized feature of AD pathology. By highlighting the tight intertwining of oligodendrocyte and myelin dynamics with tau-associated neurodegeneration, this work positions cortical myelin pathology as a potential new mechanistic and therapeutic avenue in AD.

neuroscience↗

bioRxiv2026

ST3GAL3 loss-of-function disrupts synaptic integrity and excitatory/inhibitory cortical dynamics

This study examined the role of ST3GAL3 as a regulator of excitatory/inhibitory (E/I) synaptic homeostasis using a human iPSC-based model. Neurodevelopmental disorders (NDDs) are increasingly linked to disruptions in the E/I balance, yet the molecular determinants remain poorly defined. ST3GAL3, a sialyltransferase associated with both rare monogenic disorders, including intellectual disability and infantile epilepsy, and complex polygenic conditions, such as ADHD, represents a strong candidate gene for involvement in synaptic regulation. To investigate this, isogenic ST3GAL3 knockout (ST3GAL3 KO) and wildtype (WT) iPSC lines were generated through CRISPR/Cas9 editing and differentiated into cortical neurons using both directed and induced protocols. This dual strategy enabled robust comparisons across cellular contexts and minimised methodological bias. To this end, we conducted functional characterisation using microelectrode array (MEA) technology alongside transcriptomic profiling through RNA sequencing (RNAseq), directly comparing ST3GAL3 KO-derived neurons with their isogenic controls. Functional assays using MEA revealed aberrant bursting patterns, particularly prolonged burst durations and heightened variability in S3GAL3KO neurons. Complementary transcriptomic profiling performed via RNAseq demonstrated downregulation in ST3GAL3 KO lines of genes involved in cognition, memory, as well as glutamatergic and GABAergic synaptic plasticity and functionality, providing molecular evidence for widespread synaptic dysregulation. Together, these findings establish ST3GAL3 as a key regulator of E/I balance in the cortices, advancing current knowledge on the pathophysiological involvement of ST3GAL3 deficiencies in the development of NDDs.

neuroscience↗

bioRxiv2025

A Cell Type Enrichment Analysis Tool for Brain DNA Methylation Data (CEAM)

DNA methylation signatures are highly cell type-specific, yet most epigenome-wide association studies (EWAS) are performed on bulk tissue, potentially obscuring critical cell type-specific patterns. Existing computational tools for detecting cell type-specific DNAm changes are often limited by the accuracy of cell type deconvolution algorithms. Here, we introduce CEAM (Cell-type Enrichment Analysis for Methylation), a robust and interpretable framework for cell type enrichment analysis in DNA methylation data. CEAM applies over-representation analysis with cell type-specific CpG panels from Illumina EPIC arrays derived from nuclei-sorted cortical post-mortem brains from neurologically healthy aged individuals. The constructed CpG panels were systematically evaluated using both simulated datasets and published EWAS results from Alzheimers disease, Lewy body disease, and multiple sclerosis. CEAM demonstrated resilience to shifts in cell type composition, a common confounder in EWAS, and remained accurate across a wide range of differentially methylated positions, underscoring its flexibility. Application to existing EWAS findings generated in neurodegenerative diseases revealed enrichment patterns concordant with established disease biology, confirming CEAMs biological relevance. The workflow is publicly available as an interactive Shiny app (https://um-dementia-systems-biology.shinyapps.io/CEAM/) enabling rapid, interpretable analysis of cell type-specific DNAm changes from bulk EWAS.

genomics↗

bioRxiv2025

Epigenomic subtypes of late-onset Alzheimer's disease reveal distinct microglial signatures

Growing evidence suggests that clinical, pathological, and genetic heterogeneity in late-onset Alzheimers disease contributes to variable therapeutic outcomes, potentially explaining many trial failures. Advances in molecular subtyping through proteomic and transcriptomic profiling reveal distinct patient subgroups, highlighting disease complexity beyond amyloid-beta plaques and tau tangles. This insight underscores the need to expand molecular subtyping across new molecular layers, to identify novel drug targets for different patient subgroups. In this study, we analyzed genome-wide DNA methylation data from three independent postmortem brain cohorts (n = 831) to identify epigenetic subtypes of late-onset Alzheimers disease. Unsupervised clustering approaches were employed to identify distinct DNA methylation patterns, with subsequent cross-cohort validation to ensure robustness and reproducibility. To explore the cell-type specificity of the identified epigenomic subtypes, we characterized their methylation signatures utilizing DNA methylation profiles derived from purified brain cells. Transcriptomic data from bulk and single-cell RNA sequencing were integrated to examine the functional impact of epigenetic subtypes on gene expression profiles. Finally, we performed statistical analyses to investigate associations between these DNA methylation-defined subtypes and clinical or neuropathological features, aiming to elucidate their biological significance and clinical implications. We identified two distinct epigenomic subtypes of late-onset Alzheimers disease, each defined by reproducible DNA methylation patterns across three cohorts. Both subtypes exhibit cell-type-specific DNA methylation profiles. Subtype 1 and subtype 2 show significant microglial methylation enrichment, with odds ratios (OR) of 1.6 and 1.3, respectively. The minimal overlap between them suggests distinct microglial states. Additionally, subtype 2 displays strong neuronal (OR = 1.6) and oligodendrocyte (OR = 3.6) enrichment. Bulk transcriptomic analyses further highlighted divergent biological mechanisms underpinning these subtypes, with subtype 1 enriched for immune-related processes, and subtype 2 characterized predominantly by neuronal and synaptic functional pathways. Single-cell transcriptional profiling of microglia revealed subtype-specific inflammatory states: subtype 1 represented a state of chronic innate immune hyperactivation with impaired resolution, while subtype 2 exhibited a more dynamic inflammatory profile balancing pro-inflammatory signaling with reparative and regulatory mechanisms. This study highlights the molecular heterogeneity of late-onset Alzheimers disease by identifying two epigenetic subtypes with distinct cell-type-specific DNA methylation patterns. Their alignment with previously defined molecular classifications underscores their relevance in disease pathogenesis. By linking these subtypes to inflammatory microglial activity, our findings provide a foundation for future precision medicine approaches in Alzheimers research and treatment.

genomics↗

bioRxiv2023

From methylation to myelination: epigenomic and transcriptomic profiling of chronic inactive demyelinated multiple sclerosis lesions

IntroductionIn the progressive phase of multiple sclerosis (MS), the hampered differentiation capacity of oligodendrocyte precursor cells (OPCs) eventually results in remyelination failure. We have previously shown that DNA methylation of Id2/Id4 is highly involved in OPC differentiation and remyelination. In this study, we took an unbiased approach by determining genome-wide DNA methylation patterns within chronically demyelinated MS lesions and investigated how certain epigenetic signatures relate to OPC differentiation capacity. MethodsWe compared genome-wide DNA methylation and transcriptional profiles between chronically demyelinated MS lesions and matched normal-appearing white matter (NAWM), making use of post-mortem brain tissue (n=9/group). DNA methylation differences that inversely correlated with mRNA expression of their corresponding genes were validated for their cell-type specificity in laser-captured OPCs using pyrosequencing. The CRISPR-dCas9-DNMT3a/TET1 system was used to epigenetically edit human-iPSC-derived oligodendrocytes to assess the effect on cellular differentiation. ResultsOur data show hypermethylation of CpGs within genes that cluster in gene ontologies related to myelination and axon ensheathment. Cell type-specific validation indicates a region-dependent hypermethylation of MBP, encoding for myelin basic protein, in OPCs obtained from white matter lesions compared to NAWM-derived OPCs. By altering the DNA methylation state of specific CpGs within the promotor region of MBP, using epigenetic editing, we show that cellular differentiation can be bidirectionally manipulated using the CRISPR-dCas9-DNMT3a/TET1 system in vitro. ConclusionOur data indicate that OPCs within chronically demyelinated MS lesions acquire an inhibitory phenotype, which translates into hypermethylation of crucial myelination related genes. Altering the epigenetic status of MBP can restore the differentiation capacity of OPCs and possibly boost (re)myelination.

neuroscience↗

bioRxiv2020

Meta-analysis of epigenome-wide association studies in Alzheime's disease highlights 220 differentially methylated loci across cortex

Epigenome-wide association studies of Alzheimers disease have highlighted neuropathology-associated DNA methylation differences, although existing studies have been limited in sample size and utilized different brain regions. Here, we combine data from six DNA methylomic studies of Alzheimers disease (N=1,453 unique individuals) to identify differential methylation associated with Braak stage in different brain regions and across cortex. We identify 236 CpGs in the prefrontal cortex, 95 CpGs in the temporal gyrus and ten CpGs in the entorhinal cortex at Bonferroni significance, with none in the cerebellum. Our cross-cortex meta-analysis (N=1,408 donors) identifies 220 CpGs associated with neuropathology, annotated to 121 genes, of which 84 genes have not been previously reported at this significance threshold. We have replicated our findings using two further DNA methylomic datasets consisting of a further > 600 unique donors. The meta-analysis summary statistics are available in our online data resource (www.epigenomicslab.com/ad-meta-analysis/).

genomics↗

bioRxiv2019

Methodological considerations on selection of stable reference genes for RT-qPCR in the neonatal rat brain in hypoxia and hypothermia

Real-time reverse transcription PCR (qPCR) normalized to an internal reference gene (RG), is a frequently used method for quantifying gene expression changes in neuroscience. Although RG expression is assumed to be constantly independent of physiological or experimental conditions, several studies have shown that commonly used RGs are not expressed stably. The use of unstable RGs has a profound effect on the conclusions drawn from studies on gene expression, and almost universally results in spurious estimation of target gene expression. Approaches aimed at selecting and validating RGs often make use of different statistical methods, which may lead to conflicting results. The present study evaluates the expression of 5 candidate RGs (Actb, Pgk1, Sdha, Gapdh, Rnu6b) as a function of hypoxia exposure and hypothermic treatment in the neonatal rat cerebral cortex -in order to identify RGs that are stably expressed under these experimental conditions- and compares several statistical approaches that have been proposed to validate RGs. In doing so, we first analyzed the RG ranking stability proposed by several widely used statistical methods and related tools, i.e. the Coefficient of Variation (CV) analysis, GeNorm, NormFinder, BestKeeper, and the {Delta}Ct method. Subsequently, we compared RG expression patterns between the various experimental groups. We found that these statistical methods, next to producing different rankings per se, all ranked RGs displaying significant differences in expression levels between groups as the most stable RG. As a consequence, when assessing the impact of RG selection on target gene expression quantification, substantial differences in target gene expression profiles were observed. As such, by assessing mRNA expression profiles within the neonatal rat brain cortex in hypoxia and hypothermia as a showcase, this study underlines the importance of further validating RGs for each new experimental paradigm considering the limitations of each selection method.

molecular biology↗

bioRxiv2019

Cognitive Improvements after Intermittent Deep Brain Stimulation of the Nucleus Basalis of Meynert in a Transgenic Rat Model for Alzheimer’s disease; a Preliminary Approach

BackgroundDeep brain stimulation (DBS) of the nucleus basalis of Meynert (NBM) has shown to have promising results in a pilot study with patients suffering from Alzheimers disease (AD). A recent study in aged monkeys shows a novel intermittent stimulation pattern to have superior cognitive benefits over continuous paradigms.\n\nObjective/HypothesisWe aimed at comparing the cognitive effects elicited by intermittent and continuous NBM stimulation paradigms in an animal model for AD (TgF344-AD rat line; TG), i.e. rats expressing mutant human amyloid precursor protein (APPsw) and presenilin 1 (PS1{Delta}E9) genes, each independent causes of early-onset familial AD.\n\nMethodsIn this exploratory study, aged APP/PS1 rats were tested pre-, and post implantation with several stimulation parameters, i.e. unilateral- or bilateral-intermittent, and bilateral-continuous, while performing various behavioral tasks (open field, novel object recognition, and modified Barnes maze).\n\nResults and ConclusionBilateral-intermittent NBM DBS allowed aged TG rats to perform better and maintain their performance longer in a spatial memory task, as compared to other conditions. These data support the notion that NBM DBS could be further refined in the clinic, thereby improving patient care.

neuroscience↗