Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.820703
Title: Consequences of presynaptic dysfunction in Alzheimer's Disease models
Author: Taylor, Henry
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2020
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Abstract:
Soluble oligomeric assemblies of amyloid β (Aβo) drive much of Alzheimer’s disease (AD) pathology. Among these, changes in synaptic plasticity including attenuated long-term potentiation (LTP), and facilitated long-term depression (LTD), accompanied by postsynaptic weakening, are believed to be significant contributors to disease progression. Much work has been directed at characterising the postsynaptic effects of oligomers, with little or conflicting evidence of their impact at the presynaptic bouton. Some studies investigating presynaptic boutons directly, have suggested that Aβo elevate presynaptic transmitter release. Given that transmitter release precedes postsynaptic processes, an alteration in presynaptic biology could drive postsynaptic pathology. One important downstream process of AD pathology is tau hyperphosphorylation. The relationship between Aβo and tau phosphorylation is unknown. Recent evidence that tau plays a physiological role in AMPAR endocytosis as a result of LTD induction might provide a link between tau phosphorylation and Aβo-induced synaptic changes. Here I probe the presynaptic effects of Aβo and how they impact AD pathogenesis. I confirm that Aβo can enhance both evoked, and non-evoked spontaneous miniature presynaptic release using direct, optical techniques in rat hippocampal cultures. Furthermore, I show that partial reduction in presynaptic function can restore Aβo-induced plasticity deficits in adult mouse acute hippocampal slices. I also demonstrate that these plasticity deficits might underly tau pathology; In rat organotypic slices I show that chronic NMDAR-dependent LTD can cause pathological tau phosphorylation, mimicking the effects of chronic Aβo incubation, which also requires NMDARs. In addition, I show that reduction in presynaptic function prevents Aβo-induced pathological tau phosphorylation, suggesting that the pathological tau phosphorylation that occurs in AD could be a result of repeated LTD-inducing conditions driven by an enhancement of presynaptic release probability. Previously, little work has been done to establish a role for presynaptic changes in AD. I have developed this area within the thesis and have established a link between aberrant Aβo aggregation and pathological tau phosphorylation that could have an important impact on AD therapy.
Supervisor: Emptage, Nigel ; Galione, Antony Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.820703  DOI: Not available
Keywords: Alzheimer's Disease
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