Oligodendrocyte precursor cells inageing and Alzheimer’s disease

Abstract

Oligodendrocyte precursor cells (OPCs) are a population of dividing cells and their main role is to generate oligodendrocytes, the myelinating cells of the CNS, throughout life. They express a wide range of neurotransmitter receptors and ion channels. A key feature of oligodendrocyte precursor cells is that they contact neuronal synapses and nodes of Ranvier. Synaptic communication is thought to control the dynamics (proliferation, differentiation and survival) of oligodendrocyte precursor cells. Oligodendrocyte precursor cells are essential for myelin replacement through natural ageing. In many neurodegenerative diseases such as multiple sclerosis or Alzheimer’s disease myelin is disrupted, and oligodendrocyte precursor cells fail to regenerate the myelin lost. The causes of oligodendrocyte precursor cells impairment in these cases are poorly understood. In this thesis, I analysed oligodendrocyte precursor cells in tissue from mice injected with botulinum neurotoxin in the hippocampus to investigate whether the synaptic silencing that this toxin causes influenced the morphology and dynamics of oligodendrocyte precursor cells, resulting in myelin loss. In addition, I examined oligodendrocyte precursor cells in the APP/PS1 mouse model of Alzheimer’s disease. Finally, I analysed the dynamics of oligodendrocyte precursor cells in the adult and ageing brain of the Pdgfra-CreERT2:Rosa26R-YFP mice. The results showed that synaptic silencing by botulinum neurotoxin causes reduction in oligodendrocyte precursor cells number, cell shrinkage and loss of complexity (branching, length and volume of their processes), but not loss of myelin. In the APP/PS1 mouse model, oligodendrocyte precursor cells were analysed in 9 months and 14 months old mice. The results showed decrease in oligodendrocyte precursor cells number, increase in immature oligodendrocytes, cell shrinkage and a trend towards an increase in myelination at 9 months, whereas at 14 months there was loss of oligodendrocyte precursor cells, as well as of immature oligodendrocytes and myelin, and an increase in cell complexity consistent with reaction to damage. In addition, the results showed a decrease in cells of the oligodendrocyte lineage and a slow down in the process of differentiation in the ageing brain. Overall, this thesis provides new knowledge on regulation of oligodendrocyte precursor cells by synaptic signalling and how this is related to changes in oligodendrocyte precursor cells in ageing an Alzheimer’s disease.

Date of Award	Sept 2018
Original language	English
Awarding Institution	University of Portsmouth
Supervisor	Arthur Butt (Supervisor) & Jerome Swinny (Supervisor)