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Abstract

Alzheimer's disease (AD) results from a series of dysfunctions which spread throughout the
cortex in a precise spatiotemporal manner, and which subsequently give rise to a
characteristic pattern of cognitive and non-cognitive symptoms. Whilst some of these
symptoms can be controlled with specific drug regimes, there are still no treatments
available to prevent the disease. Similarly, there are no drugs available which will reverse
or even halt the progression of the pathological changes which occur in the AD brain.
It is hypothesised that β-amyloid deposited within the brain as "plaques' causes slowly
evolving physical damage to neurons, which then triggers a stereotypical neuronal response
to trauma. This involves specific cytoskeletal alterations which give rise to the
characteristic neuropathology of AD, and which can be experimentally modeled in both in
vivo and in vitro models of neuronal injury. That the pathogenesis of AD crucially involves
the cytoskeleton, and that targeting these changes may be an effective method of delaying
or even preventing neurodegeneration in AD, was explored in this thesis.
A number of broad hypotheses were posed. Firstly, that there are significant cytoskeletal
alterations in the AD brain which may be ameliorated by the use of cytoskeletal stabilising
agents, and which may subsequently limit the evolution of the neuropathological changes
characteristic of AD. Secondly, that metallothioneins may play a role in AD, and perhaps
be able to prevent the aberrant neuronal sprouting associated with AD.
These hypotheses were addressed in a number of aims. The major conclusions from these
investigations were that morphologically distinct plaque types differentially affect the
architecture of the brain in the early and late stages of AD, to result in significant
cytoskeletal alterations. Similar observations were made following experimental cortical
injury, where it was demonstrated that the administration of cytoskeletal stabilising drugs
can both prevent and delay the onset of neuropathological changes. Finally,
metallothioneins were shown to be upregulated in both the early stages of AD and
following cortical injury, suggesting that they may have a role in the pathogenesis of AD.
This thesis has, therefore, demonstrated that it is possible to intervene in the sequence of
events which ultimately leads to neurodegeneration in AD. Agents which target
cytoskeletal alterations may represent alternatives to current therapeutic strategies.

Item Type:	Thesis - PhD
Authors/Creators:	Adlard, P
Keywords:	Alzheimer's disease
Copyright Holders:	The Author
Copyright Information:	Copyright 2000 the Author - The University is continuing to endeavour to trace the copyright owner(s) and in the meantime this item has been reproduced here in good faith. We would be pleased to hear from the copyright owner(s).
Additional Information:	Thesis (Ph.D.)--University of Tasmania, 2001. Includes bibliographical references
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