Biology subjects

Osso, L. A.

Publications and source records attributed to Osso, L. A..

3 recordsLinked to original sources

bioRxiv2026

Microglia drive demyelination via multiple sclerosis antibodies and BTK signaling

Microglia are the predominant immune cells in multiple sclerosis (MS) demyelinating lesions, where they phagocytose myelin, but whether they destroy myelin or merely scavenge its debris is unknown. Here, we explore whether pathogenic autoantibodies found in MS may induce the phagocytic destruction of myelin by microglia. Applying patient-derived, myelin-targeting antibodies to the mouse cortex, we developed an in vivo model of MS with focal demyelination that depended on epitope specificity and Fc gamma receptor and complement binding. Longitudinal monitoring of microglia-myelin interactions using in vivo two-photon microscopy revealed rapid microglial envelopment of intact myelin driving myelin loss, while single-cell RNA sequencing identified a demyelination-associated microglial signature. Parallel changes were observed in human MS lesions, where microglia enveloped intact myelin and similar genes were upregulated. Inhibition of Brutons tyrosine kinase (BTK) limited microglial transcriptional changes and prevented myelin loss following microglial envelopment. These findings directly implicate microglia in pathological myelin loss and support BTK inhibition as a therapeutic strategy to prevent demyelination by modulating microglia behavior.

neuroscience↗

bioRxiv2026

Premyelinating Oligodendrocyte Survival Governs CNS Remyelination

Myelinating oligodendrocytes are produced throughout life by the constitutive differentiation of oligodendrocyte precursor cells (OPCs). However, the rate of oligodendrocyte generation changes with age and after a demyelinating injury. Here, we report that variation in premyelinating oligodendrocyte (preOL) survival modulates the rate of oligodendrocyte production. PreOL survival increased to drive the regeneration of oligodendrocytes after demyelination and decreased in middle-aged mice to contribute to age-related decline in oligodendrocyte production. Furthermore, we demonstrate that treatment with a GPR17 antagonist, Myro-02, increases oligodendrocyte replacement by promoting preOL survival after demyelination. Together, our findings demonstrate that increased survival of preOLs governs the regeneration of oligodendrocytes following demyelinating injury and suggest that modulating preOL survival may be an alternative therapeutic avenue to promote oligodendrocyte regeneration.

neuroscience↗

bioRxiv2024

Incomplete remyelination via endogenous or therapeutically enhanced oligodendrogenesis is sufficient to recover visual cortical function

Myelin loss induces deficits in action potential propagation that result in neural dysfunction and contribute to the pathophysiology of neurodegenerative diseases, injury conditions, and aging. Because remyelination is often incomplete, better understanding endogenous remyelination and developing remyelination therapies that seek to restore neural function are clinical imperatives. Here, we used in vivo two-photon microscopy and electrophysiology to study the dynamics of endogenous and therapeutic-induced cortical remyelination and functional recovery after cuprizone-mediated demyelination in mice. We focused on the visual pathway, which is uniquely positioned to provide insights into structure-function relationships during de/remyelination. We show that endogenous remyelination is driven by recent oligodendrocyte loss and is highly efficacious following mild demyelination, but fails to restore the oligodendrocyte population when high rates of oligodendrocyte loss occur too quickly. Testing a novel thyromimetic compared to clemastine fumarate, we find it better enhances oligodendrocyte gain during remyelination and hastens recovery of neuronal function. Surprisingly, its therapeutic benefit was temporally restricted, and it acted exclusively following moderate to severe demyelination to eliminate endogenous remyelination deficits. However, complete remyelination is unnecessary as partial oligodendrocyte restoration was sufficient to recover visual neuronal function. These findings advance our understanding of remyelination and its impact on functional recovery to inform future therapeutic strategies.

neuroscience↗