Decreased Regenerative Capacity of Oligodendrocyte Progenitor Cells (NG2-Glia) in the Ageing Brain: A Vicious Cycle of Synaptic Dysfunction, Myelin Loss and Neuronal Disruption?

Abstract

Oligodendrocytes are specialised glial cells that myelinate CNS axons. Myelinated axons are bundled together into white matter tracts that interconnect grey matter areas of the brain and are essential for rapid, integrated neuronal communication and cognitive function. Life-long generation of oligodendrocytes is required for myelination of new neuronal connections and repair of myelin lost through natural 'wear and tear'. This is the function of a substantial population of adult oligodendrocyte progenitors (OPs). Notably, there is white matter shrinkage and decreased myelination in the ageing brain, which is accelerated in dementia. The underlying causes of myelin loss in dementia are unresolved, but it implies a decline in the regenerative capacity of OPs. A feature of OPs is that they form neuron-glial synapses and respond to glutamate released by neurons via a range of glutamate receptors. Glutamate neurotransmission onto OPs is proposed to regulate their proliferation and differentiation into myelinating oligodendrocytes. Here, we discuss evidence that deregulation of glutamate neurotransmission in dementia and compromised generation of oligodendrocytes from OPs are key features of myelin loss and associated cognitive decline.

White matter damage and glymphatic dysfunction in a model of vascular dementia in rats with no prior vascular pathologies

“…However, in WM diseases like multiple sclerosis and VaD, remyelination failure during disease progression eventually occurs due to impaired survival, proliferation, migration, recruitment, and differentiation of OPCs (Maki, et al, 2013). In the aging brain, there is white matter shrinkage and decreased myelination, which is exacerbated and accelerated in dementia, suggesting a decline in the regenerative capacity of OPCs (Rivera, et al, 2016). Our data show that MMI in RB rats significantly decreased the number of OPCs in the corpus callosum and striatum.…”

Promoting Neurovascular Recovery in Aged Mice after Ischemic Stroke - Prophylactic Effect of Omega-3 Polyunsaturated Fatty Acids

“…Cerebral ischemia induces white matter injury, and subsequently the young adult brain mounts and endogenous effort to stimulate proliferation of OPCs and migration towards demyelinated areas in order to differentiate into mature oligodendrocytes and restore myelin sheaths. Others have suggested that the capacity for the repair of white matter injury diminishes with increased age [ 48 , 73 , 74 ]. Our previous studies demonstrate that n-3 PUFAs preserve the integrity of white matter and enhance oligodendrogenesis in young adult mice following ischemic insults [ 23 , 75 ].…”

Accelerated dystrophy and decay of oligodendrocyte precursor cells in the APP/PS1 model of Alzheimer’s-like pathology

“…Prior to differentiating into mature myelinating oligodendrocytes, OPCs transition through an intermediate phase identified by expression of the G-protein coupled receptor GPR17 (Viganò et al, 2016). Notably, early changes in OPCs may be a pathological sign and underlie myelin loss in mouse models of AD-like pathology (Rivera et al, 2016, Vanzulli et al, 2020. This possibility is supported by immunostaining of post-mortem AD brain showing reduced NG2 immunoreactivity in individuals with high A plaque load (Nielsen et al, 2013b).…”