Determining if pre-existing inflammation affects facial motoneuronal survival

Abstract

Motor Neuron Disease (MND) is a debilitating condition affecting ageing individuals that is characterised by the death of motoneurones. Changes in the neurotrophic support of motoneurones, altered glial and synaptic activity and levels of inflammation have been proposed as mechanisms underlying MND, but these have not been considered in the light of advancing age, which is the single biggest risk factor for MND. This thesis investigates the roles of age, neurotrophic factors, perineuronal responses through glial and synaptic activity, and levels of inflammation in experimental models of rat facial motoneuronal death and rescue. It pays particular attention to an isoform of IGF-1 derived from active muscle, known as Mechano Growth Factor (MGF) and its mechanism of action. It investigates if perineuronal responses can predict the fate of injured motoneurones. It also correlates age-related changes in levels of inflammatory mediators with motoneuronal survival after injury. It reports that: (i) MGF rescues mature motoneurones by a mechanism that is independent of the IGF-1 receptor and Protein Kinase C; (ii) perineuronal responses such as glial and synaptic activity may still predict the fate of injured motoneurones; (iii) the survival of avulsed facial motoneurones increases with age and that this is associated with an increase in levels of inflammation in the CNS but not in the blood; (iv) immune-priming does not affect the survival of mature motoneurones and (v) the immune response to challenge changes with age. Results are considered in the context of current ideas on the roles of ageing, perineuronal activity, neurotrophic factors and inflammation in neuronal death and survival. It is proposed that immature and mature motoneurones respond differently to motoneurone rescue factors and changes in levels of inflammation. This calls into question some commonly held views on the mechanisms underlying age-related neuronal degeneration such as MND.