Abstract
Brain ageing is characterised by a decline in neuronal function and associated cognitive deficits. There is increasing evidence that myelin disruption is an important factor that contributes to the age‐related loss of brain plasticity and repair responses. In the brain, myelin is produced by oligodendrocytes, which are generated throughout life by oligodendrocyte progenitor cells (OPCs). Currently, a leading hypothesis points to ageing as a major reason for the ultimate breakdown of remyelination in Multiple Sclerosis (MS). However, an incomplete understanding of the cellular and molecular processes underlying brain ageing hinders the development of regenerative strategies. Here, our combined systems biology and neurobiological approach demonstrate that oligodendroglial and myelin genes are amongst the most altered in the ageing mouse cerebrum. This was underscored by the identification of causal links between signalling pathways and their downstream transcriptional networks that define oligodendroglial disruption in ageing. The results highlighted that the G‐protein coupled receptor Gpr17 is central to the disruption of OPCs in ageing and this was confirmed by genetic fate‐mapping and cellular analyses. Finally, we used systems biology strategies to identify therapeutic agents that rejuvenate OPCs and restore myelination in age‐related neuropathological contexts.
Highlights
Ageing in the brain is accompanied by a gradual decline in neuronal networking and synaptic plasticity which are needed for learning and cognitive function
Using a combined transcriptomic and neurobiology approach we have identified essential oligodendroglial genes amongst the most dysregulated in the ageing mouse cerebrum, most notably Gpr17, which decorates a subpopulation of differentiation committed oligodendrocyte progenitor cells (OPCs) (COPs) that are in transition to mature myelinating oligodendrocytes (MOLs) and react rapidly to brain pathology (Lecca et al, 2020)
Several lines of evidence show that Egfr promote oligodendrocyte regeneration and myelin repair (Aguirre et al, 2007), and our findings indicate Egfr signalling is pivotal to multiple transcriptional networks and signalling pathways that regulate age-related changes in oligodendrocytes
Summary
Ageing in the brain is accompanied by a gradual decline in neuronal networking and synaptic plasticity which are needed for learning and cognitive function. There is evidence of gradual losses in oligodendrocytes and myelin in ageing and that these changes are key factors in cognitive decline and to decreased capacity for repair following pathology (Vanzulli et al, 2020). Using a combined transcriptomic and neurobiology approach we have identified essential oligodendroglial genes amongst the most dysregulated in the ageing mouse cerebrum, most notably Gpr, which decorates a subpopulation of differentiation committed OPCs (COPs) that are in transition to mature myelinating oligodendrocytes (MOLs) and react rapidly to brain pathology (Lecca et al, 2020). We used novel in silico pharmacogenomics strategies for the identification of therapeutic agents that stimulate the transcriptional networks for driving the regeneration of OPCs following demyelination and have therapeutic potential in MS and neurodegenerative diseases
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