Abstract
Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterised by accumulation of ß-amyloid in extracellular plaques, intracellular neurofibrillary tangles composed of abnormally phosphorylated and aggregated tau, and widespread synaptic dysfunction and neuron loss that underlie the clinical symptoms of AD. Glial activation and a neuroinflammatory immune response is also a key aspect of the pathological progression of AD. The activation of astrocytes appears to be particularly associated with pathological changes in tau. This thesis aims to investigate the association between astrocyte activation and abnormal tau processing using primary cell culture and human post-mortem brain. Furthermore, it aims to explore possible regional differences in this role of astrocytes, and the molecular signalling pathways by which astrocytes exert their effects on tau.Experiments in primary astrocyte and neuron co-cultures demonstrated that astrocytes were involved in accelerating Aß-induced neurotoxicity in hippocampal cultures, but not cortical cultures although the differences were quite subtle. Interestingly, astrocytes were important for the neuronal release of tau from cortical neurons under basal conditions, suggesting that astrocytes may be important for pathological tau spread in AD. Analysis of human post-mortem brain showed differences in astrocytic changes in hippocampus and cortex as AD progresses. In addition, these experiments also suggested regional differences in mechanisms related to synaptic dysfunction and loss as disease progresses. These data suggest that different mechanisms may underlie the neurodegenerative effects of ß-amyloid and/or activated astrocytes in distinct brain regions; an important consideration when considering therapeutic strategies for AD.
In addition, the potential benefits for tauopathy of repurposing an already licenced drug with anti-inflammatory action were investigated. Despite showing significant modulation of tau phosphorylation in primary cultures, dimethyl fumarate had little influence on disease-associated tau species when tested in vivo in a mouse model of tauopathy.
Overall, the findings of this thesis suggest that there are regional differences in astrocyte activation during the development of AD, that are somewhat associated with AD-relevant changes in tau. This work also supports a role for astrocytes in physiological tau release. Further elucidating these differences will increase understanding of neurodegenerative mechanisms. Moreover, these data suggest that regional involvement at different disease stages could be an important consideration when targeting specific mechanisms for therapeutic development.
| Date of Award | 2017 |
|---|---|
| Original language | English |
| Awarding Institution |
|
| Supervisor | Wendy Noble (Supervisor) & Diane Hanger (Supervisor) |