Biology subjects

Vanherle, S.

Publications and source records attributed to Vanherle, S..

4 recordsLinked to original sources

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↗

bioRxiv2025

Resting-state functional dynamics alterations relate to plasma amyloid markers and explain memory impairments in the TgF344-AD model of Alzheimer's disease

Resting-state (RS) fMRI studies of Alzheimers diseases (AD) impact on brain function commonly use functional connectivity (FC), ignoring short-timescale network dynamics, captured by co-activation patterns (CAPs), shown to accurately classify transgenic rodents from the wild-type (WT). We acquired high temporal resolution RS-fMRI data in the TgF344-AD rat model at pre-plaque and plaque stages and delineated brain functional alterations using FC and CAPs. We also assessed plaque-stage blood amyloid levels and memory performance in the same animals and investigated the statistical relationship between pathological, RS-functional, and behavioral phenotypes. TgF344-AD (TG) rats had elevated blood amyloid levels, committed more working and reference memory errors and showed reduced hippocampal FC with the lateral cortical and default-mode-like network (DMLN) compared to WT at the plaque stage. They showed DMLN and hippocampal hyper- and hypo-activation at pre- and plaque stages respectively in multiple CAPs. While blood amyloid levels were explained better by plaque-stage, than pre-plaque stage, FC values and CAP activations, it was the pre-plaque stage, more than the plaque stage, CAP activations that accurately explained memory impairments. Our findings not only identify early signatures of AD in brain functional dynamics in this translational rat model but demonstrate their relevance for prognosis of memory deficits.

neuroscience↗

bioRxiv2024

IL-34 empowers regulatory T cells with novel non-canonical function to safeguard brain barrier integrity during neuro-inflammation.

In efforts to find reparative strategies for brain damage, brain-associated regulatory T cells (Tregs) have gained increasing attention in recent years. Beyond their textbook immunoregulatory function, Tregs have emerged as key players in the response to brain trauma and the restoration of damaged brain tissue. Here, we are the first to describe a novel, non-canonical function of Tregs in maintaining the sealing capacity of both the blood-brain barrier (BBB) and the blood-cerebrospinal fluid (CSF) barrier. Moreover, we identified the cytokine IL-34 as a critical determinant in this newly unveiled Treg function. Mechanistically, IL-34 exerts its influence by modulating the expression and localization of the tight junction protein ZO-1 in both BBB endothelial cells and choroid plexus epithelial cells, thereby reinforcing the strength of the brain barriers. Given the well-established notion of leaky brain barriers and the involvement of immunological components in neurological diseases such as Alzheimers disease (AD) and multiple sclerosis (MS), we further demonstrate diminished IL-34 expression in Tregs derived from patients with relapsing-remitting MS (RR-MS) and patients with AD and even mild cognitive impairment (MCI). Remarkably, our study reveals the potential of IL-34 treatment in reinstating the integrity of brain barriers within murine models mimicking these neurological disorders. These ground-breaking findings shed light on the intricate relationship between Tregs, IL-34, and the integrity of brain barriers. They offer novel avenues for therapeutic approaches to ameliorate brain barrier dysfunction in the context of neurological disorders.

immunology↗

bioRxiv2022

Extracellular vesicle-associated cholesterol dictates the regenerative functions of macrophages in the brain

Macrophages play major roles in the pathophysiology of various neurological disorders, being involved in seemingly opposing processes such as lesion progression and resolution. Yet, the molecular mechanisms that drive their harmful and benign effector functions remain poorly understood. Here, we demonstrate that extracellular vesicles (EVs) secreted by repair-associated macrophages (RAMs) enhance remyelination ex vivo and in vivo by promoting the differentiation of oligodendrocyte precursor cells (OPCs). Guided by lipidomic analysis and applying cholesterol depletion and enrichment strategies, we find that EVs released by RAMs show markedly elevated cholesterol levels and that cholestserol abundance controls their reparative impact on OPC maturation and remyelination. Mechanistically, EV-associated cholesterol was found to promote OPC differentiation through direct membrane fusion. Collectively, our findings highlight that EVs are essential for cholesterol trafficking in the brain and that changes in cholesterol abundance dictate the reparative impact of EVs released by macrophages in the brain, potentially having broad implications for therapeutic strategies aimed at promoting repair in neurodegenerative disorders.

neuroscience↗