{"id":{"repo_id":"cambridge","oai_identifier":"oai:www.repository.cam.ac.uk:1810/326365"},"canonical_url":"https://search.dev.ndltd.org/etd/cambridge/oai:www.repository.cam.ac.uk:1810/326365","repository":{"repo_id":"cambridge","name":"Cambridge University","base_url":"https://api.repository.cam.ac.uk/server/oai/request"},"display":{"title":"The Prostaglandin E2 Receptor Subtype 3E and its involvement in tauopathies","abstract":"Neuroinflammation is becoming increasingly recognised as key to the pathogenesis of Alzheimer’s disease and tauopthies. Epidemiological studies report a delay in the onset of Alzheimer’s in subjects using nonsteroidal anti-inflammatory drugs (NSAIDs). NSAIDs inhibit enzymes in the cyclooxygenase-2 (COX-2) pathway which play a key role in synthesising prostaglandin E2 (PGE2) from arachidonic acid. PGE2 has been implicated in preclinical stages of Alzheimer’s disease, where elevated levels of PGE2 in the cerebrospinal fluid can be found, as well as aberrant amyloid processing in experimental models of disease. PGE2 signals via 4 E-prostanoid (EP) receptors, EP1-EP4, all G-protein coupled receptors (GPCR). The EP3 receptor, the most abundant PGE2 receptor in the brain, is unique in that it is alternatively spliced giving rise to species specific isoforms. One of the EP3 receptor isoforms, EP3Re, is human specific and an incidental finding within a project to investigate its distribution in brain, suggested that it could be associated with tau tangles. The aim of this project was to further investigate the unknown distribution of EP3Re in human brain, to determine its signalling mechanism and explore whether any meaningful interaction between EP3Re, tau and its pathology exists. We use immunohistochemistry, proximity ligation assays and electron microscopy to map out the distribution of EP3Re in the human brain and explore the interaction between EP3Re and tau. We also use gene reporter and second messenger assays to characterise EP3Re signalling and what role if any this may be playing in tauopathies. We show that EP3Re is expressed throughout the brain, with strong expression in brain stem nuclei, and signals predominantly through a Gi coupling pathway. Moreover, using a combination of human tissue, primary cell lines and neurons derived from induced pluripotent stem cells, we show that EP3Re appears to be associated with tau neurofibrillary tangles in disease. We also show, using the EP3 agonist sulprostone, that signalling through the receptor increases tau phosphorylation in our cellular systems. Further work will be required to fully clarify the specificity of the interaction and understand the mechanism behind this and if targeting inflammatory EP3Re signalling has the potential to affect tau pathology in disease.","abstract_html":"Neuroinflammation is becoming increasingly recognised as key to the pathogenesis of Alzheimer’s disease and tauopthies. Epidemiological studies report a delay in the onset of Alzheimer’s in subjects using nonsteroidal anti-inflammatory drugs (NSAIDs). NSAIDs inhibit enzymes in the cyclooxygenase-2 (COX-2) pathway which play a key role in synthesising prostaglandin E2 (PGE2) from arachidonic acid. PGE2 has been implicated in preclinical stages of Alzheimer’s disease, where elevated levels of PGE2 in the cerebrospinal fluid can be found, as well as aberrant amyloid processing in experimental models of disease. PGE2 signals via 4 E-prostanoid (EP) receptors, EP1-EP4, all G-protein coupled receptors (GPCR). The EP3 receptor, the most abundant PGE2 receptor in the brain, is unique in that it is alternatively spliced giving rise to species specific isoforms. One of the EP3 receptor isoforms, EP3Re, is human specific and an incidental finding within a project to investigate its distribution in brain, suggested that it could be associated with tau tangles. The aim of this project was to further investigate the unknown distribution of EP3Re in human brain, to determine its signalling mechanism and explore whether any meaningful interaction between EP3Re, tau and its pathology exists. We use immunohistochemistry, proximity ligation assays and electron microscopy to map out the distribution of EP3Re in the human brain and explore the interaction between EP3Re and tau. We also use gene reporter and second messenger assays to characterise EP3Re signalling and what role if any this may be playing in tauopathies. We show that EP3Re is expressed throughout the brain, with strong expression in brain stem nuclei, and signals predominantly through a Gi coupling pathway. Moreover, using a combination of human tissue, primary cell lines and neurons derived from induced pluripotent stem cells, we show that EP3Re appears to be associated with tau neurofibrillary tangles in disease. We also show, using the EP3 agonist sulprostone, that signalling through the receptor increases tau phosphorylation in our cellular systems. Further work will be required to fully clarify the specificity of the interaction and understand the mechanism behind this and if targeting inflammatory EP3Re signalling has the potential to affect tau pathology in disease.","abstract_has_math":false,"creators":["Briggs, Mayen"],"institution":"University of Cambridge","degree_name":"Doctor of Philosophy (PhD)","degree_level":"Doctoral","degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":["Spillantini, Maria Grazia"],"committee_chairs":[],"committee_members":[],"year":2021,"date_issued":"2021-06-01","date_published":"2021-06-01","updated_at":"2026-07-22T22:24:24Z","subjects":["tau","PGE2","Progressive supranuclear palsy","Inflammation","EP3","Alzheimer's","EP receptor"],"languages":["eng"],"rights":[],"rights_urls":["https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/857804d5-f5a3-499f-9bf2-e8adf4d6701a/download","https://www.rioxx.net/licenses/all-rights-reserved/"],"identifier_entries":[]},"links":{"outbound_url":"https://doi.org/10.17863/CAM.73823","outbound_label":"DOI","outbound_source":"dc:identifier.doi"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Spillantini, Maria Grazia"]},{"key":"dc:contributor.sponsor","label":"Sponsor","values":["John Van Geest studentship; Alzheimer's Research UK (ARUK)"]},{"key":"dc:creator","label":"Author","values":["Briggs, Mayen"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.issued","label":"Date","values":["2021-06-01"]},{"key":"dc:publisher.institution","label":"Dc Publisher Institution","values":["University of Cambridge"]},{"key":"dc:relation.isreferencedby.uri","label":"Dc Relation Isreferencedby URI","values":["https://www.repository.cam.ac.uk/handle/1810/326365"]},{"key":"dc:type","label":"Dc Type","values":["Thesis"]},{"key":"dc:type.qualificationlevel","label":"Dc Type Qualificationlevel","values":["Doctoral"]},{"key":"dc:type.qualificationname","label":"Dc Type Qualificationname","values":["Doctor of Philosophy (PhD)"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["tau","PGE2","Progressive supranuclear palsy","Inflammation","EP3","Alzheimer's","EP receptor"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["eng"]},{"key":"dc:rights","label":"Dc Rights","values":["https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/857804d5-f5a3-499f-9bf2-e8adf4d6701a/download","https://www.rioxx.net/licenses/all-rights-reserved/"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.doi","label":"DOI","values":["10.17863/CAM.73823"]},{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/cb3f1fa7-b5a2-4875-89b8-9e77b02c1a5f/download"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Neuroinflammation is becoming increasingly recognised as key to the pathogenesis of Alzheimer’s disease and tauopthies. 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The aim of this project was to further investigate the unknown distribution of EP3Re in human brain, to determine its signalling mechanism and explore whether any meaningful interaction between EP3Re, tau and its pathology exists. We use immunohistochemistry, proximity ligation assays and electron microscopy to map out the distribution of EP3Re in the human brain and explore the interaction between EP3Re and tau. We also use gene reporter and second messenger assays to characterise EP3Re signalling and what role if any this may be playing in tauopathies. We show that EP3Re is expressed throughout the brain, with strong expression in brain stem nuclei, and signals predominantly through a Gi coupling pathway. Moreover, using a combination of human tissue, primary cell lines and neurons derived from induced pluripotent stem cells, we show that EP3Re appears to be associated with tau neurofibrillary tangles in disease. We also show, using the EP3 agonist sulprostone, that signalling through the receptor increases tau phosphorylation in our cellular systems. 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The aim of this project was to further investigate the unknown distribution of EP3Re in human brain, to determine its signalling mechanism and explore whether any meaningful interaction between EP3Re, tau and its pathology exists. We use immunohistochemistry, proximity ligation assays and electron microscopy to map out the distribution of EP3Re in the human brain and explore the interaction between EP3Re and tau. We also use gene reporter and second messenger assays to characterise EP3Re signalling and what role if any this may be playing in tauopathies. We show that EP3Re is expressed throughout the brain, with strong expression in brain stem nuclei, and signals predominantly through a Gi coupling pathway. Moreover, using a combination of human tissue, primary cell lines and neurons derived from induced pluripotent stem cells, we show that EP3Re appears to be associated with tau neurofibrillary tangles in disease. We also show, using the EP3 agonist sulprostone, that signalling through the receptor increases tau phosphorylation in our cellular systems. 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