Title : NF- ?B is a critical mediator of age-dependent white matter loss
Abstract:
Infl ammaging represents an accepted concept where the immune system shifts to a low-grade chronic pro- infl ammatory state without overt infection upon aging. In the CNS, infl ammaging is mainly driven by glia cells and associated with neurodegenerative processes. White matter degeneration is a well-described process in the aging brain which manifests in myelin loss fi nally resulting in neurological defi cits. However, understanding of the underlying molecular mechanisms remains limited. Oligodendrocytes and their precursor cells are responsible for production, homeostasis and maintenance of the myelin sheaths. Mature oligodendrocytes are highly energy demanding cells due to their unique functions, and thus highly sensitive to different forms of stress. So far it is open how altered infl ammatory conditions like infl ammaging affect homeostasis and function of oligodendrocytes. We investigated the role of NF-κB, a well-known mediator of infl ammatory and stress responses, in the homeostatic control of oligodendrocytes using a conditional gain-of-function mouse model allowing oligodendrocyte-specifi c activation of IKK/NF-κB signaling (IKK2-CAPLP-CreERT2) in the adult organism. Chronic NF-κB activation in mature oligodendrocytes was suffi cient to initiate overall neuroinfl ammatory conditions in the CNS accompanied by motoric and neurological defi cits which progress with age. Ultrastructural analyses revealed degeneration of the corpus callosum as well as loss of myelin sheaths and accordingly, myelin proteins were found decreased in IKK2-CAPLPCreERT2 mice. Interestingly, RNA-Seq analysis of isolated primary oligodendrocytes revealed gene expression signatures pointing to NF-κB mediated Integrated Stress Response (IRS), Senescence Associated Secretory Phenotype (SASP) and Post Mmitotic Cellular Senescence (PoMiCS) appearing prior to white matter loss. Taken together, our data indicate that IKK/NF-κB signaling, a central effector of diverse stress responses, is able to trigger PoMiCS of mature oligodendrocytes thereby disturbing myelin maintenance and fi nally forcing aging-dependent white matter loss.
What will audience learn from your presentation?
- Selective NF-κB activation in mature oligodendrocytes is able to initiate global neuroinfl ammation in
- the brain
- Post-mitotic cellular senescence of mature oligodendrocytes is critically regulated by NF-κB/
- infl ammaging
- Integrated stress responses and cellular senescence are important mediators of white matter loss
- Cell-type-specifi c interference with NF-κB function or downstream effectors offer new therapeutic
- strategies to attenuate age-dependent white matter degeneration
