Restricted to everyone for three years. Restriction lift date: 2027-09-30T10:32:44Z
Examining potential causes of neuronal dysfunction in Alzheimer’s disease
| dc.check.date | 2027-09-30T10:32:44Z | |
| dc.check.embargoformat | Apply the embargo to the hard bound thesis (If you have not submitted an e-thesis and want to embargo the hard bound thesis in UCC Library) | en |
| dc.check.entireThesis | Entire Thesis Restricted | |
| dc.check.info | Restricted to everyone for three years | en |
| dc.check.opt-out | Yes | en |
| dc.check.reason | This thesis is due for publication or the author is actively seeking to publish this material | en |
| dc.contributor.advisor | Boland, Barry | en |
| dc.contributor.author | Jaisimha, Anirudh Vinay | |
| dc.date.accessioned | 2019-10-01T10:32:44Z | |
| dc.date.issued | 2019 | |
| dc.date.submitted | 2019 | |
| dc.description.abstract | Alzheimer’s disease (AD) is a debilitating neurodegenerative disease that is characterised by a number of intraneuronal hallmarks, which include the accumulation of autophagic vacuoles (AVs) within dystrophic neurites, and neurofibrillary tangles (NFTs) composed of both truncated and full-length forms of tau protein. Work presented in this thesis, outlines findings from three lines of investigation that set out to determine potential causative factors that contribute to AD-related neurodegeneration. For Aim 1, I investigated the role of impaired lysosomal digestion as a cause of AV accumulation in AD. Having developed a novel assay that utilised the detection of specific truncated forms of amyloid precursor protein C-terminal fragments (APP-CTFs), which preferentially accumulate when lysosomal digestion is impaired, findings from post-mortem human brain tissue at different Braak stages of AD (0 – VI), indicate that the accumulation of AVs in the AD brain is not caused by an impairment in lysosomal digestion. For Aim 2, I investigated the role of altered glucose availability as a cause of tau hyperphosphorylation in AD. To determine if excessive or insufficient amounts of glucose availability to neurons is a direct cause of tau hyperphosphorylation in the AD brain, I utilised a primary rat neuron culture system, to determine if hyperglycaemic or hypoglycaemic stress could lead to tau hyperphosphorylation. Despite finding high basal amounts of the AD-related tau phospho-epitope (PHF1), in both primary neurons and mouse brain, I did not report any change in levels of phospho-tau under glucose altering conditions, suggesting these changes are not directly responsible for inducing tau hyperphosphorylation in AD. For Aim 3, I investigated the role of dysfunctional neuron-glial interactions as a cause of truncation tau in AD. Having identified truncated forms of tau as early as Braak stage II in post-mortem human brain tissue, I subsequently found that neurons grown in co-cultures with glial cells, develop truncated forms of tau after two weeks in culture, which correlated with the progressive proliferation of astrocytes and microglia. I also found that certain excitatory stimuli, in particular glutamate and zinc, produced a rapid but transient increase in truncated tau, which was prevented by kynurenic acid (KynA). Concluding thoughts from all three investigations suggest that dysfunctional neuron-glial interactions are likely to occur early in AD pathogenesis and the therapeutic targeting of autonomous (neuronal) or non-autonomous (glial-mediated) factors that contribute to dysregulated neuronal excitation may prove to be beneficial in treating AD. | en |
| dc.description.status | Not peer reviewed | en |
| dc.description.version | Accepted Version | |
| dc.format.mimetype | application/pdf | en |
| dc.identifier.citation | Jaisimha, A. V. 2019. Examining potential causes of neuronal dysfunction in Alzheimer’s disease. PhD Thesis, University College Cork. | en |
| dc.identifier.uri | https://hdl.handle.net/10468/8652 | |
| dc.language.iso | en | en |
| dc.publisher | University College Cork | en |
| dc.rights | © 2019, Anirudh Vinay Jaisimha. | en |
| dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/3.0/ | en |
| dc.subject | Lysosome | en |
| dc.subject | APP-CTFs | en |
| dc.subject | Neuron-Glia interactions | en |
| dc.subject | Glucose metabolism and AD | en |
| dc.subject | Autophagy | en |
| dc.subject | Alzheimer's disease | en |
| dc.thesis.opt-out | true | |
| dc.title | Examining potential causes of neuronal dysfunction in Alzheimer’s disease | en |
| dc.type | Doctoral thesis | en |
| dc.type.qualificationlevel | Doctoral | en |
| dc.type.qualificationname | PhD | en |
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