Whole-Mitew_Thesis_-2013.pdf (19.46 MB)
Axonal and synaptic pathology in Alzheimer's disease
thesisposted on 2023-05-26, 01:48 authored by Mitew, S
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 ˜í‚â§-amyloid (A˜í‚â§) 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 A˜í‚â§ plaque-mediated cytoskeletal alterations compared to a neurofilament-rich pyramidal neuron population. Secondly, to examine the relationship between A˜í‚â§ 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 A˜í‚â§ plaque-mediated dystrophy as neurofilament-rich neurites. Moreover, GABAergic synaptic density was not significantly decreased in proximity to A˜í‚â§ 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 A˜í‚â§ 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 A˜í‚â§ plaques in mediating cytoskeletal dystrophic changes and specific synaptic loss. It also identified the novel finding of focal demyelination associated with A˜í‚â§ 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.
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