Anatomical Society Summer Meeting Glasgow 2021: Cutting Edge Anatomy

Oligodendrocytes (OLs) are specialised glial cells that myelinate axons in the central nervous system (CNS).Myelinated axons are bundled together into white matter (WM) tracts that are essential for rapid, integrated neronal communication and cognitive function.A population of adult oligodendrocyte progenitor cells (OPCs) is responsible for the life-long generation of OLs, which is essential to replace myelin lost in pathology.Recently, we have demonstrated that there is a marked loss of OPCs in the ageing murine bran, which is associated with the loss of WM and cognitive decline.To examine the underlying causes of age-related myelin loss in humans, we performed an in silico transcriptomic analysis of Intralobular WM of human samples from the UK Brain Expression Consortium (UKBEC), and samples were assigned to one of two age groups: young (18-31, n = 20) or old (71-96, n = 20).Differential expression (DE) analysis identified a marked decline in oligodendroglial genes, including the OPC gene PDGFRA and the myelin genes MBP and MOBP, supporting our recent findings in mice.Functional protein-protein network and Gene Ontology (GO) analyses highlighted that the biological pathways most disrupted in ageing human WM were involved in Neurogenesis, Cognition and CNS Development.Moreover, pathway analysis identified age-related perturbation of G-Protein Receptor Signalling and MAPK Signalling pathways, which are known to be key regulators of oligodendrogenesis and myelination.Next, we used a pharmacogenomic and functional protein-chemical network analysis approach to discover potential therapies for rejuvenating OPCs in the ageing human brain, and the result shows that the PI3K/AKT/ MTOR signalling pathway was one of the most important therapeutic targets to stimulate oligodendrogenesis in the ageing human WM.To test this, we used the WM model of mouse optic nerve organotypic culture and demonstrate the PI3K/AKT modulator LY294002 profoundly promotes oligodendrogenesis.These studies determine key changes in OLs that underlie the decline in myelination in the ageing brain.Furthermore, we identify drugs that target pro-oligodendroglial signalling pathways as potential new therapies for promoting the life-long generation of OLs and maintaining cognitive function.Human Data were obtained from publicly available datasets (GSE46706).Animal studies were performed in accordance UK Animals Scientific Procedures Act, 1984.