Functional genomic analyses highlight a shift in Gpr17‐regulated cellular processes in oligodendrocyte progenitor cells and underlying myelin dysregulation in the aged mouse cerebrum

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.

Replenishing the Aged Brains: Targeting Oligodendrocytes and Myelination?

“…For instance, genetic-fate mapping showed gradual decrease of GPR17 expression in OPCs in aging cerebrum. Moreover, in this study, GPR17 was believed to be a major factor affected during OL degeneration in the aging brain (Rivera et al, 2021). Apelin receptor (APJ) is a newly identified G-protein-coupled receptor, which could regulate OPCs differentiation through Myrf signal.…”

“…OPCs are present within and around the demyelination lesions in the aged MS model mice, but fail to differentiate and form new myelin, suggesting that in those pathological context, age-related differentiation arrest of OPCs may also be an important cause of remyelination failure ( Gilson and Blakemore, 1993 ; Sim et al, 2002 ; Goldschmidt et al, 2009 ; Ruckh et al, 2012 ). Interestingly, Metformin or LY294002 treatment, or environmental modulation by replacing young macrophages could recover the capacity of OPCs differentiation and remyelination in the aged mice ( Ruckh et al, 2012 ; Neumann et al, 2019a ; Rivera et al, 2021 ).…”

Oligodendrocytes in the aging brain

“…Recent studies using careful transcriptomic analyses of mouse brains across lifespan have characterised changes in expression of key receptors and ion channels in OPCs with age. These include the G-protein coupled receptor Gpr17 [ 125 ], NMDA and kainite glutamate receptors [ 126 ], and voltage-gated sodium and potassium channels [ 126 ]. These are all important regulators of OPC excitability and differentiation, so age-related changes in expression towards an aged OPC phenotype correlate with decreased regenerative capabilities.…”

“…As well as cell surface receptors, molecules to alter transcriptional regulation may also be beneficial to drive OPCs into a more differentiative state. For example, the mTOR signalling pathway is known to be a strong regulator of OPC differentiation, and the small molecule, LY294002, has been identified as a transcriptional regulator of this pathway with the ability to rejuvenate aged OPCs into a more primed phenotype [ 125 ].…”

The synaptic blocker botulinum toxin A decreases the density and complexity of oligodendrocyte precursor cells in the adult mouse hippocampus

“…It will be of considerable interest in future studies to determine whether synaptic blockade has longer term effects on myelination that is required for the formation of new neuronal connections and learning (McKenzie et al, 2014; Xiao et al, 2016). Notably, disruption of OPCs has been shown to result in impaired myelination in aging (Neumann et al., 2019; Rivera et al., 2021), and this is a key factor in the age‐related decline in cognitive function (Bartzokis, 2004), as well as the failure of remyelination in chronic MS (Sanai et al, 2016), and the accelerated loss of myelin observed in AD (Nasrabady et al, 2018; Vanzulli et al, 2020). In conclusion, disruption of OPCs following synaptic blockade in the hippocampus is relevant to cognitive function and neuropathologies where there is dysregulation of neuronal synaptic activity.…”