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Axonal and synaptic pathology in Alzheimer’s disease


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Mitew, S 2013 , 'Axonal and synaptic pathology in Alzheimer’s disease', PhD thesis, University of Tasmania.

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The cause of the initial synaptic disconnection and eventual widespread neuronal
degeneration that underlies the onset and progressive development of dementia in
sufferers of Alzheimer’s disease (AD) remains elusive. The pathognomonic features
of AD, extracellular accumulations of soluble and fibrillar β-amyloid (Aβ) as well as
intracellular neurofibrillary tangles comprised of hyperphosphorylated tau, that give
rise to characteristic dystrophic neurites and neuropil threads, respectively, have been
studied extensively in human AD cases and a variety of transgenic mouse models.
Nonetheless, the degree to which these malformations affect different populations of
neurons and their synaptic connections in the cortex remains to be defined.
Furthermore, although white matter degeneration has previously been implicated in
AD, not much is known about the extent of myelin loss in AD. This thesis, therefore,
sought to address four aims analyzing the relationship between AD pathology and
the mechanisms underlying AD. Firstly, to investigate the extent to which
interneuron subpopulations are susceptible to Aβ plaque-mediated cytoskeletal
alterations compared to a neurofilament-rich pyramidal neuron population. Secondly,
to examine the relationship between Aβ plaque deposition and inhibitory and
excitatory synaptic connections. Thirdly, to assess if the activity of glutamate
decarboxylase, the enzyme catalysing the formation of the inhibitory
neurotransmitter GABA, is altered in a transgenic mouse model of AD. Finally, to
determine if AD pathology is associated with cortical demyelination and
oligodendrocyte cell loss in human and transgenic mice.
The major conclusions drawn from these investigations were that inhibitory
interneuron neurites were not as susceptible to Aβ plaque-mediated dystrophy as neurofilament-rich neurites. Moreover, GABAergic synaptic density was not
significantly decreased in proximity to Aβ plaques unlike excitatory glutamatergic
synapse density. These decreases were accompanied by potentially compensatory
changes in presynaptic bouton size, perisomatic innervation, as well as increased
gliotransmission of GABA in Aβ plaque-rich neuropil. Neuritic plaque deposition
was also associated with focal demyelination and concomitant decreases in several
integral myelin-associated proteins. Interestingly, although mature oligodendrocyte
loss was also present, there were significant increases in the number of immature
oligodendrocytes and precursor cells, indicative of a reactive remyelinating response.
In summary, this thesis further clarified the pathological role of Aβ plaques in
mediating cytoskeletal dystrophic changes and specific synaptic loss. It also
identified the novel finding of focal demyelination associated with Aβ deposits. A
better understanding of these early pathological alterations in the progression of AD
is necessary for the development of effective therapeutic strategies. In particular, the
compensatory changes in response to ongoing AD pathology could offer promising
endogenous targets for slowing or repairing neuronal dysfunction.

Item Type: Thesis - PhD
Authors/Creators:Mitew, S
Keywords: Alzheimer's disease, Beta-amyloid, dystrophic neurite, interneunon, neurofilament, triplet, synapse loss
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