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Epigenetic reactivation of oligodendroglial cells in Alzheimer’s disease

Project description

Delaying Alzheimer’s disease

Alzheimer’s disease remains one of medicine’s greatest unsolved challenges. Most therapies and interventions have failed to demonstrate clinical efficacy in trials. A key reason may be that research has focused mainly on neurons, overlooking the critical role of supporting brain cells. The ERC-funded EpiGlia project proposes to target oligodendrocytes, whose function declines with age and is strongly disrupted in Alzheimer’s disease. These cells are responsible for maintaining the insulating sheaths around nerve fibres. Using precision epigenetic tools, researchers will map age-related molecular changes in these cells and identify specific genetic targets for reactivation. The goal of the EpiGlia approach is to complement existing therapies and open new avenues for treating Alzheimer’s and other neurodegenerative diseases.

Objective

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.

Fields of science (EuroSciVoc)

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Keywords

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Programme(s)

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Topic(s)

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Funding Scheme

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HORIZON-ERC - HORIZON ERC Grants

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Call for proposal

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(opens in new window) ERC-2025-COG

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Host institution

UNIVERSITE D'AIX MARSEILLE
Net EU contribution

Net EU financial contribution. The sum of money that the participant receives, deducted by the EU contribution to its linked third party. It considers the distribution of the EU financial contribution between direct beneficiaries of the project and other types of participants, like third-party participants.

€ 1 999 799,00
Address
BOULEVARD CHARLES LIVON 58 LE PHARO
13284 Marseille
France

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Region
Provence-Alpes-Côte d’Azur Provence-Alpes-Côte d’Azur Bouches-du-Rhône
Activity type
Higher or Secondary Education Establishments
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Total cost

The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.

€ 1 999 799,00

Beneficiaries (1)

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