Biology subjects

Vanmierlo, T.

Publications and source records attributed to Vanmierlo, T..

7 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↗

bioRxiv2026

The ApoC2 mimetic peptide D6PV enhances remyelination by stimulating oxidative phosphorylation in oligodendrocytes

Failure of remyelination drives neurodegeneration in demyelinating disorders such as multiple sclerosis (MS), with disrupted lipid handling and metabolic stress in oligodendrocyte precursor cells (OPCs) posing major barriers to repair. Here, we identify the dual ApoC-II mimetic-ApoC-III antagonist peptide D6PV as a metabolic modulator that directly enhances OPC differentiation and myelin repair. Across ex vivo and in vivo models of chemically induced demyelination, D6PV promotes oligodendrocyte maturation and restores myelin integrity independently of lipoprotein hydrolysis or modulation of lipid droplet-containing phagocytes. Guided by transcriptomics analyses, we find that D6PV stimulates mitochondrial oxidative phosphorylation and fatty acid {beta}-oxidation, while suppressing inflammatory transcriptional programs, thereby driving OPCs toward a myelinating phenotype. Notably, D6PV does not alter peripheral immune composition or autoimmune-driven pathology in the experimental autoimmune encephalomyelitis model, indicating a central nervous system (CNS) cell-autonomous effect. These findings reveal a metabolism-linked pathway for remyelination and position D6PV as a promising therapeutic strategy to enhance CNS repair in demyelinating diseases.

neuroscience↗

bioRxiv2023

Amelioration of Functional and Histopathological Consequences after Spinal Cord Injury through Phosphodiesterase 4D (PDE4D) Inhibition

Spinal cord injury (SCI) is a life-changing event that severely impacts the patients quality of life. Two key strategies are currently being considered to improve clinical outcomes after SCI: modulation of the neuroinflammatory response, which exacerbates the primary injury, and stimulation of neuro-regenerative repair mechanisms to improve functional recovery. Cyclic adenosine monophosphate (cAMP) is a second messenger crucially involved in both processes. Following SCI, intracellular levels of cAMP are known to decrease over time. Therefore, preventing cAMP degradation represents a promising strategy to suppress inflammation while stimulating regeneration. Intracellular cAMP levels are controlled by its hydrolyzing enzymes phosphodiesterases (PDEs). The PDE4 family is most abundantly expressed in the central nervous system (CNS) and its inhibition has been shown to be therapeutically relevant for managing SCI pathology. Unfortunately, the use of full PDE4 inhibitors at therapeutic doses is associated with severe emetic side effects, hampering their translation toward clinical applications. Therefore, in this study, we evaluated the effect of inhibiting specific PDE4 subtypes (PDE4B and PDE4D) on inflammatory and regenerative processes following SCI, as inhibitors selective for these subtypes have been demonstrated to be well-tolerated. We reveal that administration of the PDE4D inhibitor Gebr32a, but not the PDE4B inhibitor A33, improved functional as well as histopathological outcomes after SCI, comparable to results obtained with the full PDE4 inhibitor roflumilast. Furthermore, using a luminescent human iPSC-derived neurospheroid model, we show that PDE4D inhibition stabilizes neural viability by preventing apoptosis and stimulating neuronal differentiation. These findings strongly suggest that specific PDE4D inhibition offers a novel therapeutic approach for SCI.

neuroscience↗

bioRxiv2023

Carnosine synthase deficiency aggravates neuroinflammation in multiple sclerosis

Multiple sclerosis (MS) pathology features autoimmune-driven neuroinflammation, demyelination, and failed remyelination. Carnosine is a histidine-containing dipeptide (HCD) with pluripotent homeostatic properties that is able to improve outcomes in an animal MS model (EAE) when supplied exogenously. To uncover if endogenous carnosine is involved in, and protects against, MS-related neuroinflammation, demyelination or remyelination failure, we here studied the HCD-synthesizing enzyme carnosine synthase (CARNS1) in human MS lesions and two preclinical mouse MS models (EAE, cuprizone). We demonstrate that due to its presence in oligodendrocytes, CARNS1 expression is diminished in demyelinated MS lesions and mouse models mimicking demyelination/inflammation, but returns upon remyelination. Carns1-KO mice that are devoid of endogenous HCDs display exaggerated neuroinflammation and clinical symptoms during EAE, which could be partially rescued by exogenous carnosine treatment. Worsening of the disease appears to be driven by a central, not peripheral immune-modulatory, mechanism possibly linked to impaired clearance of the reactive carbonyl acrolein in Carns1-KO mice. In contrast, the presence of CARNS1 and endogenous HCDs does not protect against cuprizone-induced demyelination, and is not required for normal oligodendrocyte precursor cell differentiation and (re)myelin to occur. Exogenously administered carnosine is not effective in blunting demyelination or accelerating remyelination. In conclusion, we show that CARNS1 is diminished in demyelinated MS lesions, which may have detrimental effects on disease progression through weakening the endogenous protection against neuroinflammation.

neuroscience↗

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↗

bioRxiv2022

Therapeutic administration of mouse mast cell protease 6 improves functional recovery after traumatic spinal cord injury in mice by promoting remyelination and reducing glial scar formation

Traumatic spinal cord injury (SCI) most often leads to permanent paralysis due to the inability of axons to regenerate in the adult mammalian central nervous system (CNS). In the past, we have shown that mast cells (MCs) improve the functional outcome after SCI by suppressing scar tissue formation at the lesion site via mouse mast cell protease 6 (mMCP6). In this study, we investigated whether recombinant mMCP6 can be used therapeutically to improve the functional outcome after SCI. Therefore, we applied mMCP6 locally via an intrathecal catheter in the subacute phase after a spinal cord hemisection injury in mice. Our findings showed that hind limb motor function was significantly improved in mice that received recombinant mMCP6 compared to the vehicle-treated group. In contrast to our previous findings in mMCP6 knockout mice, the lesion size and expression levels of the scar components fibronectin, laminin, and axon-growth-inhibitory chondroitin sulfate proteoglycans were not affected by the treatment with recombinant mMCP6. Surprisingly, no difference in infiltration of CD4+ T cells and reactivity of Iba-1+ microglia/macrophages at the lesion site was observed between the mMCP6-treated mice and control mice. Additionally, local protein levels of the pro- and anti-inflammatory mediators IL-1{beta}, IL-2, IL-4, IL-6, IL-10, TNF-, IFN{gamma}, and MCP-1 were comparable between the two treatment groups, indicating that locally applied mMCP6 did not affect inflammatory processes after injury. However, the increase in locomotor performance in mMCP6-treated mice was accompanied by reduced demyelination and astrogliosis in the perilesional area after SCI. Consistently, we found that TNF-a/IL-1B-astrocyte activation was decreased, and that oligodendrocyte precursor cell (OPC) differentiation was increased after recombinant mMCP6 treatment in vitro. Mechanistically, this suggests effects of mMCP6 on reducing astrogliosis and improving (re)myelination in the spinal cord after injury. In conclusion, these data show for the first time that recombinant mMCP6 is therapeutically active in enhancing recovery after SCI.

neuroscience↗