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Pathological changes leading to neuronal degeneration in Alzheimer's disease

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Woodhouse, Adele (2008) Pathological changes leading to neuronal degeneration in Alzheimer's disease. PhD thesis, University of Tasmania.

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Abstract

Alzheimer' s disease (AD) is the most common form of dementia. The pathological
hallmarks of AD include ß-amyloid (Aß) plaques, dystrophic neurites (DNs) and
neurofibrillary tangles (NFTs). All of these pathological hallmarks involve abnormal
insoluble proteinaceous aggregates that have the capacity to disturb normal cellular
functioning. However, there is disagreement within the AD literature as to whether it is
Aß plaques, soluble Aß or NFTs that are the primary causative agent of AD.
Irrespective of the initial cause of AD, the burden of Aß plaques and NFTs increases as
AD progresses, eventually resulting in substantial brain atrophy, which is at least
partially due to overt neuronal degeneration and death. Thus, a better understanding of
the aetiology and progression of AD will enable more efficient therapeutics to be
developed.
This thesis investigates the role of apoptosis in AD with the aim of ascertaining whether
apoptosis is involved in disease staging or progression or is a causative agent of AD. No
increase in immunohistochemical labelling, or change in localisation that distinguished
between control, preclinical AD and AD cases were present for a range of apoptosis-related
proteins. In addition, mRNA levels of apoptosis-related proteins differed little
between control, preclinical AD and AD cases when analysed by real time reverse
transcriptase polymerase chain reaction. There was no difference in the percentage of
apoptotic-like nuclei in the neocortex between control, preclinical AD and AD cases and
very few of the nuclei associated with Aß plaques or NFTs were abnormal. Cytochrome
c (cyto c)-labelling was punctate in cortical neurons, including a subset of NFT-bearing
neurons, but a subset of DNs demonstrated cytoplasmic cyto c-labelling. These data
suggest that apoptosis may not play a major role in the pathogenesis or progression of
AD and that activation of apoptotic pathways can occur in the absence of extensive
terminal appptosis in the brain.
As post-mortem human AD tissue provides only random time points in the dynamic
process of disease progression, transgenic mouse models of AD are invaluable tools for
investigating aspects of age-associated disease progression and also for testing potential
therapeutics for AD. Although, for animal models to be used effectively, a detailed
understanding of the pathology and disease processes that they model is required.
Therefore, the AP plaque-associated neuronal pathology in two transgenic AD mouse
models was investigated to determine whether the neuronal pathology in these mice
more closely resembles human preclinical AD cases or clinically evident AD cases.
Using immunohistochemistry the morphology and neurochemistry of the AP plaque-associated
DNs present in the two lines of transgenic AD mice was demonstrated to be
strikingly similar to that in human preclinical AD cases, but not AD cases. Importantly,
quantitation demonstrated that the Aß plaques in these transgenic AD mice were highly
axonopathic, and were also associated with displaced or clipped apical dendrites in both
transgenic mouse models. The results suggest that these mice represent an accurate and
valuable model of preclinical AD that can be utilised as a platform for testing potential
therapeutic agents for AD, to be administered prior to extensive neuronal loss.
Finally, as current treatments for AD only treat the symptoms of the disease and do not
slow or stop its progression, the potential of a novel therapeutic agent with zinc binding,
neuroprotective and anti-oxidant properties, metallothionein isoform IIA (MTIIA), was
investigated. Utilising immunohistochemistry, the Aß and thioflavine s plaque loads
and the Aß plaque-associated neuronal pathology in 13 and 15 month old Tg2576 mice
was investigated after three months of metallothionein IIA treatment. Although this
pilot study did not produce any statistically significant results, there was a trend towards
lower Aß and thioflavine s plaque loads in MTIIA treated Tg2576 mice. Thus, MTIIA
warrants further investigation as a potential therapeutic for AD in the future.
The research in this thesis provides valuable new data on the staging of AD, with
particular regard to the role of apoptosis in AD and Aß plaque-associated neuronal
pathology in transgenic AD mice and human AD. The current study indicates that
apoptosis does not play a seminal role in the genesis or progression of AD pathology.
This works has also clarified how two widely studied transgenic AD mice compare to
the schema of disease progression that occurs in human AD, and strongly suggests that
these transgenic AD mice mimic human preclinical AD. Finally, a pilot study of MTIIA
administration to transgenic AD mice did not result in significant differences between
the treatment and control groups.

Item Type: Thesis (PhD)
Keywords: Alzheimer's disease
Copyright Holders: The Author
Copyright Information:

Copyright 2008 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:

Available for library use only and copying in accordance with the Copyright Act 1968, as amended. Thesis (PhD)--University of Tasmania, 2008. Includes bibliographical references

Date Deposited: 04 Feb 2015 23:34
Last Modified: 11 Mar 2016 05:53
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