Keeping the ageing brain wired: a role for purine signalling in regulating cellular metabolism in oligodendrocyte progenitors

Abstract

White matter (WM) is a highly prominent feature in the human cerebrum and is comprised of bundles of myelinated axons that form the connectome of the brain. Myelin is formed by oligodendrocytes and is essential for rapid neuronal electrical communication that underlies the massive computing power of the human brain. Oligodendrocytes are generated throughout life by oligodendrocyte precursor cells (OPCs), which are identified by expression of the chondroitin sulphate proteoglycan NG2 (Cspg4), and are often termed NG2-glia. Adult NG2+ OPCs are slowly proliferating cells that have the stem cell–like property of self-renewal and differentiation into a pool of ‘late OPCs’ or ‘differentiation committed’ OPCs(COPs) identified by specific expression of the G-protein-coupled receptor GPR17, which are capable of differentiation into myelinating oligodendrocytes. In the adult brain, these reservoirs of OPCs and COPs ensure rapid myelination of new neuronal connections formed in response to neuronal signalling, which underpins learning and cognitive function. However, there is an age-related decline in myelination that is associated with a loss of neuronal function and cognitive decline. The underlying causes of myelin loss in ageing are manifold, but a key factor is the decay in OPC ‘stemness’ and a decline in their replenishment of COPs, which results in the ultimate failure of myelin regeneration. These changes in ageing OPCs are underpinned by dysregulation of neuronal signalling and OPC metabolic function. Here, we highlight the role of purine signalling in regulating OPC self-renewal and the potential importance of GPR17 and the P2X7 receptor subtype in age-related changes in OPC metabolism. Moreover, age is the main factor in the failure of myelination in chronic multiple sclerosis and myelin loss in Alzheimer’s disease, hence understanding the importance of purine signalling in OPC regeneration and myelination is critical for developing new strategies for promoting repair in age-dependent neuropathology.

Epidermal Growth Factor Pathway in the Age-Related Decline of Oligodendrocyte Regeneration

“…However, the regenerative power of OPCs declines with age leading to impaired oligodendrogenesis and myelin remodeling, and an overall gradual loss of major CNS functions such as spatial learning and memory (Pan et al, 2020 ; Steadman et al, 2020 ; Wang et al, 2020 ). The age-related impairments in OPC differentiation have been discussed in a number of recent reviews (for example, Rivera et al, 2021a ; Butt et al, 2019 ). Moreover, in many age-related neuropathologies such as AD or secondary progressive MS, due to a number of reasons that include and are not limited to the inflammatory environment, excess inhibitory myelin debris, lack of appropriate trophic support, etc, OPC differentiation drastically fails and contributes to the loss in cognitive function (Neumann et al, 2019 ; Wang et al, 2020 ; Coelho et al, 2021 ; Rivera et al, 2021a , b ).…”

“…The age-related impairments in OPC differentiation have been discussed in a number of recent reviews (for example, Rivera et al, 2021a ; Butt et al, 2019 ). Moreover, in many age-related neuropathologies such as AD or secondary progressive MS, due to a number of reasons that include and are not limited to the inflammatory environment, excess inhibitory myelin debris, lack of appropriate trophic support, etc, OPC differentiation drastically fails and contributes to the loss in cognitive function (Neumann et al, 2019 ; Wang et al, 2020 ; Coelho et al, 2021 ; Rivera et al, 2021a , b ). Currently, the development of treatments to halt these changes is hampered by gaps in fundamental scientific knowledge.…”

The Influence of Virus Infection on Microglia and Accelerated Brain Aging

“…Accelerated brain aging is often related to enhanced neurodegeneration, which includes loss of neuronal cell structure and function due to (1) metabolic changes [ 18 ], (2) neuronal cell death [ 19 ] (3) decline in the neuronal network [ 20 ], (4) neuronal functional deficiency [ 21 ], (5) decline in neuronal regeneration [ 22 , 23 , 24 ], or (6) a combination of the mentioned reasons. It also includes functional and structural changes of the glial cells, resulting in demyelination and gliosis [ 25 , 26 , 27 ]. Neurodegeneration is aggravated by neuroinflammation, which contributes substantially to accelerated brain aging.…”

Understanding normal brain aging

“…This issue of Pflügers Archiv-European Journal of Physiology provides a series of review articles and original papers focusing on different key aspects of (patho)physiological brain aging including changes in energy provision [8], the age-dependent accumulation of reactive oxygen/ nitrogen/carbonyl species [8,14], aging of the brain vasculature including the key glial cells involved [2,17] as well as age-related decline in brain wiring [6,13,16,17] and network function [4,6]. Moreover, we focus on the two sensory systems (hearing and olfaction), prone to significant age-related deterioration.…”

“…Finally, many articles of this special issue compare aging of brain architecture and function (including sensory processing, cognitive abilities, and sleep) between humans and commonly used laboratory animals (rats and mice) [4,8,[12][13][14][15]17]. The common mechanisms identified in these studies shall enable high-resolution analyses of key cellular/ molecular pathways involved as well as the future development of therapeutics supporting the cognitive longevity or even reverting the age-induced impairment of cognition.…”