Why White Matter Matters

The massive computing power of the brain depends on myelinated fibres that are bundled together into the white matter (WM). Rapid neural communication depends on the life-long production of myelin by oligodendrocytes, which are generated from oligodendrocyte precursor cells (OPCs). Neurotransmitters released by neurons regulate the differentiation of OPCs into oligodendrocytes. Although lacking neuronal synapses, experimental studies on WM support a model of neurotransmitters being released from axons during action potential propagation to regulate myelination, with prominent roles for glutamatergic, purinergic (ATP and adenosine) and GABAergic signalling. Notably, myelination declines in the ageing brain, which is associated with cognitive decline and white matter loss in Alzheimer’s disease (AD). Our studies provide evidence that OPCs are disrupted in the ageing brain and that this is accelerated in mouse models of Alzheimer’s disease. This is correlated with a dysregulation of neurotransmitter signalling in ageing WM of the mouse optic nerve, comparable to that described in the GM of human ageing brain and AD. This lead us to propose a vicious cycle of altered neurotransmitter signaling, impaired OPC regenerative potential and myelin loss, which may be important in the loss of WM in AD.