Epigenetic reactivation of oligodendroglial cells in Alzheimer’s disease

2026-07-22

Alzheimer’s Disease (AD) is the most prominent neurodegenerative disease, representing a major public health issue worldwide. Unfortunately, the failure rate in clinical trials of AD drugs is one of the highest. One explanation could be our incompletely understanding of disease onset and progression. Notably the role of glial cells in AD has been overlooked until recently. EpiGlia aims at reactivating oligodendroglial cells to delay AD onset, by leveraging cell-specific and locus-targeted epigenetic tools. Indeed, the oligodendroglial cell lineage, by its myelinating role, plays a crucial role in the function and plasticity of the adult brain. But myelination declines in age-related diseases such as AD, which is strongly associated with cognitive decline. Epigenetic markers such as DNA modifications known to correlate with age, are also strongly dysregulated in oligodendroglial cells, and in AD tissues. However, the causal role of oligodendroglial cell defects in the pathogenesis of AD remains largely unknown. EpiGlia hypothesizes that epigenetic reactivation of oligodendroglial cells could directly limit AD pathogenesis. My proposal is built around 3 main objectives: Aim 1: MAP. Mapping of age-related epigenetic oligodendroglial dysregulation in AD pathology, by combining behavioral assays with spatial transcriptomic. Aim 2: TARGET. Targeting specific loci to epigenetically reactivate oligodendroglial cells in AD, by leveraging cell-specific tools. Aim 3: RESCUE. Rescuing oligodendroglial cells to delay AD onset, using non-invasive delivery methods in animal models. The impact for human health is underscored by the urgent need for improved therapies to treat AD. Targeting glial cells complements the current neurocentric approaches, to successfully reduce AD symptoms. These cell- and locus-specific epigenetic tools could be extended to other cell types and disease models to further leverage epigenetic reactivation in neurodegenerative diseases.

France

2026-02-15