Parkinson’s disease is an age related progressive neurodegenerative disorder
affecting ~2% of the population over the age of 65. The aetiology of Parkinson’s
disease is not fully understood and treatment limited. Hence, the goal of ongoing
research is to understand and target the mechanisms underlying the disease process to
halt or slow down its progression. Parkinson’s disease is pathologically characterised by
the loss of dopaminergic neurons in the substantial nigra that leads to the loss of
innervation to the striatum, subsequently leading to the motor complications observed in
Parkinson’s sufferers.
Recent clinical and experimental evidence suggests that inflammation,
characterised by over activation of the brain’s resident immune cells such as
microglia/macrophages, play a detrimental role in Parkinson’s pathology. This project,
for the first time aims to explore the time course of microglial activation in association
with dopaminergic neuronal cell death in the substantia nigra utilising the 6-hydroxy
dopamine rat model of Parkinson’s. The dynamics of morphological,
immunophenotypic and phagocytic properties of activated microglia in the substantia
nigra was assessed immunohistochemically. In addition we explored the cellular events
between activated microglia and degenerating neurons in this model that had not been
previously well defined. The role of matrix metalloproteinases as signalling molecules
that activate microglia were also studied. Finally the significance of local microglial
activation in the substantia nigra was elucidated by modulation of the microglial
response via activation of the gamma subtype of peroxisome proliferator activated
receptors. This project provided evidence that microglial activation preceded
dopaminergic neuronal cell death in the substantia nigra and inhibition of microglial
response serves as a neuroprotective strategy in Parkinson’s disease.