Epigenetic reactivation of oligodendroglial cells in Alzheimer’s disease

Descripción del proyecto

Retrasar la aparición de la enfermedad de Alzheimer

La enfermedad de Alzheimer constituye uno de los mayores retos sin resolver de la medicina. La mayoría de los tratamientos e intervenciones no han demostrado eficacia clínica. Una de las posibles razones es que gran parte de la investigación se ha centrado en las neuronas, mientras que el papel de otras células nerviosas de sostén ha recibido menos atención. En el proyecto EpiGlia, financiado por el Consejo Europeo de Investigación, se estudiarán los oligodendrocitos, cuya función disminuye con la edad y está muy alterada en la enfermedad de Alzheimer. Estas células se encargan de mantener las vainas de mielina de las fibras nerviosas. El equipo del proyecto empleará herramientas epigenéticas de alta precisión para identificar cambios moleculares asociados al envejecimiento en oligodendrocitos, así como identificar dianas genéticas susceptibles de reactivación. El enfoque desarrollado en EpiGlia pretende complementar las terapias existentes y abrir nuevas vías para el tratamiento de la enfermedad de Alzheimer y de otros trastornos neurodegenerativos.

Objetivo

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.