Project description
A new way to rejuvenating the ageing brain
Cognitive ageing often points to neuronal vulnerability, yet emerging evidence suggests that early dysfunction in oligodendrocytes – crucial cells responsible for myelin formation – could be a significant driver of cognitive decline. Myelin, a plastic structure that wraps around axons, adapts in response to experiences but exhibits reduced functionality in ageing. The ERC-funded OligoAging project investigates this phenomenon, focusing on how myelin plasticity is regulated by oligodendrocyte precursor cells. Researchers aim to unravel the transcriptional mechanisms behind oligodendrogenesis, explore the impact of rejuvenating cues from young cerebrospinal fluid, and identify the molecular basis for myelin decline with age. Insights gained could pave the way for innovative therapies targeting myelin health and cognitive rejuvenation.
Objective
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.
Fields of science (EuroSciVoc)
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CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques.
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Keywords
Programme(s)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Topic(s)
Funding Scheme
HORIZON-ERC - HORIZON ERC GrantsHost institution
7610001 Rehovot
Israel