OLIGODENDROGLIAL AGING: THE MISSING LINK IN ALZHEIMER’S DISEASE PATHOGENESIS?

Although long overlooked, oligodendroglial cells have emerged as key players in Alzheimer's disease (AD). Through myelination, the oligodendroglial lineage is crucial for brain function and cognition. However, myelination declines with age, the major risk factor for AD. This impairment is attributed to alterations in adult oligodendroglial cells, including epigenetic changes. We have shown that the activating DNA hydroxymethylation mark (primarily catalyzed by TET1 in the oligodendroglial lineage) is a key regulator of adult myelination, but becomes defective with aging. Therefore, I hypothesize that age-related epigenetic dysregulation of oligodendroglial cells contributes to the onset of AD. Here, we use the 5xFAD model crossed with a strain that mimics age-associated epigenetic modifications in oligodendroglial cells (TET1cKO). We show that 3-month-old 5xFAD mice develop motor learning deficits, before the onset of memory deficits (unaltered until 9 months of age). A 3-month-old cohort of 5xFAD-Tet1cKO present poorer memory, compared to age-matched 5xFAD or TET1cKO, suggesting that age-related dysregulation of oligodendroglia could aggravate AD pathogenesis. In 5xFAD mice, alterations seem independent of the oligodendrocyte progenitor cell pool, which remains stable until 6 months. Spatial transcriptomic analysis from 3-month-old WT and 5xFAD brains reveals dysregulation of oligodendroglial pathways, including neuro-oligodendroglial communication. Decline could also be related to amyloid deposits, detected at 3 months. These results highlight the potential correlation between early transcriptional changes in oligodendroglial cells and decline in learning at Alzheimer's disease onset. Overall, this project aims at assessing the burden of aging oligodendroglia in AD, which could lead to non-neurocentric therapies.