The Presynaptic and Postsynaptic Signaling of Amyloid β Protein During Ischemia

Palmer, Laura Ann

The Presynaptic and Postsynaptic Signaling of Amyloid β Protein During Ischemia

dc.contributor.advisor	Thompson, Roger J.
dc.contributor.author	Palmer, Laura Ann
dc.contributor.committeemember	Teskey, G. Campbell
dc.contributor.committeemember	Stys, Peter K.
dc.date	2019-11
dc.date.accessioned	2019-06-12T16:59:51Z
dc.date.available	2019-06-12T16:59:51Z
dc.date.issued	2019-06-11
dc.description.abstract	Amyloid β has been implicated in the pathophysiology of Alzheimer disease (AD) by disrupting synapses and enhancing cell death. Genetic mutations that are causative of familial Alzheimer disease are associated with enhanced Aβ burden. Since only 5% of AD cases are genetic, efforts must be made to understand environmental risk factors and other co-morbidities that could elevate Aβ. For instance, ischemic stroke is associated with increased risk of developing AD, which is thought to be due to enhanced production of Aβ. Loss of key energy substrates during ischemia initiate overactive synaptic glutamate release, reversed glutamate uptake, ionic dysregulation, and the anoxic depolarization. The anoxic depolarization is mediated by a number of channels, including NMDARs and pannexin-1 (Panx1) to induce Ca2+ dysregulation and downstream cell death. The role of Aβ during the events of acute ischemia is unknown, and is assumed to be pathological due to similar features of ischemia and AD. However, Aβ has been shown to depress synapses and enhance cell survival during excitotoxicity. The overarching hypothesis of this thesis is that Aβ acts to depress aberrant synaptic events during ischemia and reduces excitotoxicity. Here, I show that Aβ potently reduces excitotoxic currents during the anoxic depolarization and prevents Panx1-dependent secondary currents in response to NMDA overstimulation. Aβ does not directly inhibit Panx1 but regulates its opening by acting as an antagonist for mGluR1. This Aβ-mGluR1 interaction also enhances GABAergic signalling to reduce excitotoxic glutamate release, however, presynaptic release does not determine the magnitude of the anoxic depolarization. These data reveal a novel modulation of Panx1 opening by mGluR1, which is regulated by Aβ. Aβ production could be increased during hypoxia to reduce activation of Panx1, thereby attenuating the anoxic depolarization and downstream cell death pathways. With prolonged/repeated ischemic events, Aβ could reach toxic levels and coincide with hallmark pathophysiology of AD.	en_US
dc.identifier.citation	Palmer, L. A. (2019). The Presynaptic and Postsynaptic Signaling of Amyloid β Protein During Ischemia (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca.	en_US
dc.identifier.doi	http://dx.doi.org/10.11575/PRISM/36632
dc.identifier.uri	http://hdl.handle.net/1880/110491
dc.language.iso	eng	en_US
dc.publisher.faculty	Cumming School of Medicine	en_US
dc.publisher.institution	University of Calgary	en
dc.rights	University of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission.	en_US
dc.subject	Stroke	en_US
dc.subject	Alzheimer's Disease	en_US
dc.subject	Amyloid β	en_US
dc.subject.classification	Neuroscience	en_US
dc.title	The Presynaptic and Postsynaptic Signaling of Amyloid β Protein During Ischemia	en_US
dc.type	doctoral thesis	en_US
thesis.degree.discipline	Medicine – Neuroscience	en_US
thesis.degree.grantor	University of Calgary	en_US
thesis.degree.name	Doctor of Philosophy (PhD)	en_US
ucalgary.item.requestcopy	true