OligoAging · Uncovering the molecular mechanisms of oligodendrocyte plasticity in cognitive aging.

Myelin, an oligodendrocyte membrane spirally wrapped around axons, has only recently been appreciated to be a plastic structure, which constantly remodels in response to experience. Myelin plasticity is based on proliferation and maturation of oligodendrocyte precursor cells (OPCs) to form new myelinating oligodendrocytes (oligodendrogenesis), in conjunction with remodelling of myelin that is already established. The cellular and molecular mechanisms governing myelin plasticity and how it contributes to aging-related cognitive decline remain mostly unknown. Whereas cognitive aging is often attributed to neuronal vulnerability, here I propose that early oligodendrocyte dysfunction is a key driver of cognitive decline. I recently found that oligodendrocytes in the aging brain react to rejuvenating cues arising from young cerebrospinal fluid (CSF), with substantial effects on their cellular function and memory consolidation. Mechanistically, I identified the transcription factor serum response factor (SRF) to be necessary in oligodendrocytes for developmental myelination (Iram et al, bioRxiv), and showed that SRF is downregulated with age and induced by young CSF (Iram et al., Nature). Strikingly, oligodendrocytes remain susceptible to microenvironmental cues even at late stages of aging, positioning them as promising targets for therapeutic interventions.Combining genetic, optogenetic, and transcriptomic tools with cutting-edge whole proteome metabolic labelling, I will pursue three complementary objectives: 1) Uncover the transcriptional regulation of oligodendrocyte plasticity and aging. 2) Elucidate the molecular basis of failed oligodendrogenesis in aged mice. 3) Define mechanisms underlying decline in myelin plasticity with age by nascent proteome tagging. Completion of this work will have a profound impact on our understanding of how oligodendrocytes age and provide novel targets for brain rejuvenation through improving myelin health and integrity.