Alzheimer??s disease (AD) is the most common form of dementia affecting the elderly. Extracellular deposition of beta amyloid (Abeta plaques), intraneuronal tau accumulation, inflammation (activated astrocytes and microglia), and neuronal loss are all consistent pathological features of the disease. Unlike Abeta plaques, inflammation correlates with neuronal loss and cognitive decline in AD, suggesting it plays an important role in disease progression. Recent research has also identified soluble oligomeric Abeta species in the AD brain, which correlate with disease progression and are proposed to be more neurotoxic than their fibrillar counterpart. The main aims of this thesis were to determine whether oligomeric Abeta is a more powerful stimulator of the inflammatory response compared to fibrillar forms of the protein, to identify potential mediators of this response and to determine downstream neuronal changes. Isolated human primary astrocytic, microglial and neuronal cell cultures were used to assess which Abeta alloform and conformation was more neurotoxic and neuroinflammatory. A total of 17 inflammatory cytokines and chemokines were measured simultaneously using a Multiplex approach and neurotoxicity was assessed by lactate dehydrogenase release. Cell cultures involving all three cell types were also used to examine these inflammatory mediators in a more complex system, and direct changes in tau levels and/or phosphorylation determined by western immunoblotting. Further immunohistochemical analysis determined the localisation of oligomeric Abeta within post-mortem human AD brain tissue. The data clearly shows that oligomeric Abeta was more neurotoxic and neuroinflammatory than fibrillar Abeta, with oligomeric Abeta40 favoured in toxic plaque deposits in AD brain tissue. Cell culture experiments showed that glia clearly mediate neuroprotection against oligomeric Abeta. Soluble TNF-alpha, IL-2, IL-4 and IL-12 mediate this response early in disease, with a decline in their secretion and a sustained increase in IL-1alpha, IFN-gamma, GM-CSF, MIP-1beta, and IL-8 provoking increased tau protein expression. Overall, the data clearly demonstrates oligomeric Abeta more powerfully stimulates a suite of inflammatory mediators affecting neuronal survival and tau pathology, although the contribution of additional glial-derived factors must also be determined. The identification of these inflammatory mediators, in combination with other potential factors, may lead to the development of mechanistic therapeutic interventions that could target these early pathological changes.
| Identifer | oai:union.ndltd.org:ADTP/272488 |
| Date | January 2008 |
| Creators | Warden, Lolita Airlie, Clinical School - Prince of Wales Hospital, Faculty of Medicine, UNSW |
| Publisher | Awarded By:University of New South Wales. Clinical School - Prince of Wales Hospital |
| Source Sets | Australiasian Digital Theses Program |
| Language | English |
| Detected Language | English |
| Rights | http://unsworks.unsw.edu.au/copyright, http://unsworks.unsw.edu.au/copyright |
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