White matter protection in ageing through innovative nutrients

The human brain white matter - in particular the myelin - is a major neuroanatomical substrate of higher cognition. Brain ageing is accompanied by white matter shrinkage and myelin loss (Peters, 2009). The cells responsible for myelination in the central nervous system (CNS), i.e. oligodendrocytes, have an altered proliferation and differentiation profile in ageing, and this leads to myelination deficits (Wang and Yang, 2014). We have shown that nutrients such as omega-3 polyunsaturated fatty acids (PUFA) have significant neuroprotective potential in the CNS, either on their own or in multi-nutrient preparations (Huang et al 2007; Ward et al 2010; Pallier et al 2015). In previous studies we observed significant protection of oligodendrocytes. In the present proposal, we aim to study the impact of selected nutrients specifically on oligodendrocytes and their capacity to produce myelin. This will ultimately enable the identification and development of combinations of nutrients which support white matter integrity and promote healthy brain ageing. It has been shown that specific lipids (e.g. palmitic acid or palmitoyl-phosphatidylcholine) have therapeutic potential when systemically administered in demyelinating disorders, e.g. multiple sclerosis (Ho et al., 2012). We will explore this concept and develop a brain protective approach applicable in the general population, to prevent white matter ageing. In healthy individuals brain myelin breakdown starts in middle-age, therefore there is ample opportunity for nutrient-based approaches to alter the course of this process (Bartzokis et al 2010). We will analyse the effects of selected nutrients in: i) primary mouse oligodendrocyte progenitor cell (OPC) cultures (to characterize intrinsic effects on OPC and the myelin synthesis capacity), ii) oligodendrocyte-neuronal co-cultures (to characterize the effects on myelin sheath formation), and iii) organotypic slices (to carry out electrophysiological studies, hence assess the functional impact of improved myelin). Lipids constitute around 70% of the myelin sheath, therefore the nutrients tested will be with priority lipids, such as PUFA, and simple or complex phospholipids, ceramides, gangliosides and sulfatides. Nutrients will be tested under basal conditions and also using stimuli which mimic natural factors which create oligodendrocyte stress, accelerate brain ageing and promote neurodegeneration, i.e. ischaemia (oxygen-glucose deprivation), inflammation (lipopolysaccharide) and excitotoxicity (e.g. glutamate and various glutamate receptor ligands) (Schmitz et al 2012).The effects will be assessed by immunocytochemistry and western blot for myelin proteins, lipidomic mass spectrometry for myelin lipids, and electrophysiological recordings for functional outcome. The selected nutrients with positive effects on oligodendrocytes and myelin will ultimately be tested in vivo in a model of induced CNS demyelination in aged rats (12-15 months).