Abstract
Synapse loss in Alzheimer’s disease (AD) is the best correlate of cognitive impairment. However, the processes underlying synapse loss in AD are still not sufficiently understood. Synaptic proteins have been traditionally used as markers to investigate synaptic degeneration and loss, however, these have not been fully able to predict when changes in disease first occur. The neuroprotective co-chaperone protein, cysteine string protein (CSP) alpha is involved in the maintenance of protein folding, neurotransmitter release and synaptic stability. Further, it has been shown that CSPalpha can be secreted in association with neurodegenerative disease proteins such as tau, a process likely linked with “prion-like” propagation of protein aggregates across AD brain. Previous work in the Giese laboratory suggested a protective role for CSPalpha during the early stages of presynaptic degeneration in AD. This thesis builds on these findings to add new data showing the accumulation of CSPalpha near AD-associated Aβ plaques in post-mortem human brain and describes the relationship between CSPalpha and amyloid pathology.Results are presented showing amorphous accumulations of CSPalpha near the core of Aβ deposits, that partially colocalise with hyperphosphorylated tau, dystrophic neurites and in glial cells proximal to plaques. CSPalpha is highly expressed in presynaptic terminals, and the accumulations of CSPalpha were found to localise to some, but not all dystrophic presynaptic structures, suggesting a possible or intra- or extracellular localisation. Using super resolution microscopy and array tomography, CSPalpha accumulations were found to exist in close proximity to Aβ deposits, to a greater extent than other presynaptic proteins such as synaptophysin. Varying levels of CSPalpha protein expression was identified in other neurodegenerative diseases including mixed dementia, frontotemporal lobar dementia and dementia with Lewy bodies, along with evidence of CSPalpha accumulations but only in the presence of amyloid plaques. Furthermore, in the brains of the 5x familial AD (FAD) mice, which display memory impairments related to Aβ over-production and the development of amyloid plaques, it was found that virtually all of the Aβ-positive deposits were associated with aberrant CSPalpha accumulations.
These findings suggest a novel role for CSPalpha as a pathological marker of presynaptic damage that is associated with Aβ pathology. These findings are in-line with published reports of dystrophic presynaptic terminal structures and presynaptic protein deposits surrounding amyloid plaques. However, CSPalpha accumulations were more abundant and were also found distal from the amyloid plaque centre in comparison to other presynaptic proteins. Together these data indicate that CSPalpha may be the earliest known pathological marker of pre-synapse loss in diseases that feature Aβ deposition and may also mediate neuroprotective and/or neurodegenerative mechanisms in disease. These findings further support pre-synaptic die-back theories in AD and provide a better understanding of synapse degeneration in several neurodegenerative diseases.
| Date of Award | 1 Jun 2021 |
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| Original language | English |
| Awarding Institution |
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| Supervisor | Peter Giese (Supervisor) & Wendy Noble (Supervisor) |