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), the 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), which are enriched in certain food, such as cold water fish, have significant neuroprotective potential in the CNS, either on their own or in specialised multi-nutrient preparations (Huang et al 2007; Ward et al 2010; Pallier et al 2015). In previous studies we observed significant protection of oligodendrocytes with such interventions, in the context of tissue damage.
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) glial mixed cultures and oligodendrocyte -neuronal co-cultures (the latter will allow us to characterize the effects on myelin sheath formation), and iii) organotypic slices (to carry out electrophysiological studies, hence assess the functional properties 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 analysis 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, for example in a model of induced CNS demyelination in aged rats (12-15 months) (Shields et al, 1999), to assess the ability to reverse an age-dependent remyelination deficit.
The identification of specific nutrients which support formation of myelin will advance the knowldege on the dynamics of myelin formation and thus the data generated in this project will make a contribution to the characterization of the neurobiology of myelin, as many aspects of myelin formation and consolidation are incompletely understood; the findings in this study also have a practical implication, that of possible development of a commercial preparation which could be made widely available, to prevent myelin senescence, on the scale of whole populations – and therefore the results of the project could have a major public health impact.
Interested applicants are encouraged to contact Prof. Adina Michael-Titus (A.T.Michael-Titus@qmul.ac.uk) in advance of the deadline.
Closing date is 19th January. Please ensure that you read the Guidelines before submitting an application. Your application and supporting documents should be sent in a single email to LIDo.Admissions@ucl.ac.uk
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