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postgraduate thesis: The examination of endothelin-1 effects on vascular-neurodegenerative pathways contributing to cognitive impairment

TitleThe examination of endothelin-1 effects on vascular-neurodegenerative pathways contributing to cognitive impairment
Authors
Advisors
Issue Date2013
PublisherThe University of Hong Kong (Pokfulam, Hong Kong)
Citation
Ho, W. K. [何慧盈]. (2013). The examination of endothelin-1 effects on vascular-neurodegenerative pathways contributing to cognitive impairment. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. Retrieved from http://dx.doi.org/10.5353/th_b5177340
AbstractAlzheimer’s disease and vascular dementia are the leading causes of cognitive disorders in the elderly worldwide. Increasing cases with overlaps in neuropathology between both disorders are becoming evident, giving rise to the concept of “mixed dementia”, which is characterized by cerebrovascular dysregulations along with tauopathies and β-amyloid (Aβ)-associated neurotoxicity. While the exact mechanisms leading to the exhibited vascular-neurodegenerative pathophysiology are still unclear, it is often found that ischemic-stroke contributes to amyloid pathogenesis, thus exacerbating cognitive impairment. Astrocytes, the most abundant cell type in the brain, appear to be important mediators in the central nervous system homeostasis and pathophysiology. This study proposes that upon ischemic stress, endothelin-1 (ET-1) overexpression in astrocytes leads to β-site APP cleaving enzyme 1 (BACE1) upregulation, hence contributing to enhanced amyloid pathology. ET-1 is a potent vasoconstrictor associated to Aβ pathogenesis in the brain, and BACE1 is the rate-limiting enzyme for Aβ synthesis. In order to assess astrocytic responses to ischemic stress, two previously modified astrocytic cell lines, mock-transfected control astrocytes (WT) and ET-1 overexpressing astrocytes (C6), were used. The exposures of WT and C6 cells to oxygen and glucose deprivation (OGD) – to mimic ischemic stress in vitro – evoked no abrupt differences between both cell lines. After OGD, astrocytes were characterized by cellular swelling, detachment from neighboring cells, increased cell death, decreased cell proliferation, and reduced BACE1 expressions during reperfusion. In addition, the attempt to modulate BACE1 protein levels, by blocking the receptor for advanced glycation end products, induced no significant differences. This study also investigated astrocytic ET-1 influences in the neuropathology of the transgenic mouse models APPGET-1 (amyloid precursor protein and astrocytic ET-1 overexpression) and GET-1 through a proteomics approach. The abnormal expressions of tropomyosin-3, transgelin-3, ATP synthase α chain, 3-hydroxyisobutyrate dehydrogenase, superoxide dismutase 1, glutathione S-transferase P1, and peroxiredoxin-6 in the mice hippocampi were identified. It is most likely that these proteins participate in cytoskeleton structural changes, energy metabolism impairment, and oxidant-antioxidant system imbalances that contribute to the observed increased brain atrophy displayed in these two animal models. In summary, this study has identified the possible participation of several proteins in the accelerated declination of cognitive functions exhibited by GET-1 and APPGET-1 mice through a proteomics approach. However, our in vitro results suggest that ET-1 did not play any pivotal role in C6 response to the hypoxic conditions evaluated. Furthermore, results showed no correlation between astrocytic ET-1 and BACE1. Further investigations examining alternative BACE1-independent pathways are required to elucidate the intricate relationship between ET-1 and Aβ in astrocytes.
DegreeMaster of Philosophy
SubjectEndothelins
Cognition disorders
Dept/ProgramPsychiatry
Persistent Identifierhttp://hdl.handle.net/10722/196432

 

DC FieldValueLanguage
dc.contributor.advisorLaw, ACK-
dc.contributor.advisorChung, SK-
dc.contributor.authorHo, Wendy Karen-
dc.contributor.author何慧盈-
dc.date.accessioned2014-04-11T23:14:22Z-
dc.date.available2014-04-11T23:14:22Z-
dc.date.issued2013-
dc.identifier.citationHo, W. K. [何慧盈]. (2013). The examination of endothelin-1 effects on vascular-neurodegenerative pathways contributing to cognitive impairment. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. Retrieved from http://dx.doi.org/10.5353/th_b5177340-
dc.identifier.urihttp://hdl.handle.net/10722/196432-
dc.description.abstractAlzheimer’s disease and vascular dementia are the leading causes of cognitive disorders in the elderly worldwide. Increasing cases with overlaps in neuropathology between both disorders are becoming evident, giving rise to the concept of “mixed dementia”, which is characterized by cerebrovascular dysregulations along with tauopathies and β-amyloid (Aβ)-associated neurotoxicity. While the exact mechanisms leading to the exhibited vascular-neurodegenerative pathophysiology are still unclear, it is often found that ischemic-stroke contributes to amyloid pathogenesis, thus exacerbating cognitive impairment. Astrocytes, the most abundant cell type in the brain, appear to be important mediators in the central nervous system homeostasis and pathophysiology. This study proposes that upon ischemic stress, endothelin-1 (ET-1) overexpression in astrocytes leads to β-site APP cleaving enzyme 1 (BACE1) upregulation, hence contributing to enhanced amyloid pathology. ET-1 is a potent vasoconstrictor associated to Aβ pathogenesis in the brain, and BACE1 is the rate-limiting enzyme for Aβ synthesis. In order to assess astrocytic responses to ischemic stress, two previously modified astrocytic cell lines, mock-transfected control astrocytes (WT) and ET-1 overexpressing astrocytes (C6), were used. The exposures of WT and C6 cells to oxygen and glucose deprivation (OGD) – to mimic ischemic stress in vitro – evoked no abrupt differences between both cell lines. After OGD, astrocytes were characterized by cellular swelling, detachment from neighboring cells, increased cell death, decreased cell proliferation, and reduced BACE1 expressions during reperfusion. In addition, the attempt to modulate BACE1 protein levels, by blocking the receptor for advanced glycation end products, induced no significant differences. This study also investigated astrocytic ET-1 influences in the neuropathology of the transgenic mouse models APPGET-1 (amyloid precursor protein and astrocytic ET-1 overexpression) and GET-1 through a proteomics approach. The abnormal expressions of tropomyosin-3, transgelin-3, ATP synthase α chain, 3-hydroxyisobutyrate dehydrogenase, superoxide dismutase 1, glutathione S-transferase P1, and peroxiredoxin-6 in the mice hippocampi were identified. It is most likely that these proteins participate in cytoskeleton structural changes, energy metabolism impairment, and oxidant-antioxidant system imbalances that contribute to the observed increased brain atrophy displayed in these two animal models. In summary, this study has identified the possible participation of several proteins in the accelerated declination of cognitive functions exhibited by GET-1 and APPGET-1 mice through a proteomics approach. However, our in vitro results suggest that ET-1 did not play any pivotal role in C6 response to the hypoxic conditions evaluated. Furthermore, results showed no correlation between astrocytic ET-1 and BACE1. Further investigations examining alternative BACE1-independent pathways are required to elucidate the intricate relationship between ET-1 and Aβ in astrocytes.-
dc.languageeng-
dc.publisherThe University of Hong Kong (Pokfulam, Hong Kong)-
dc.relation.ispartofHKU Theses Online (HKUTO)-
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License-
dc.rightsThe author retains all proprietary rights, (such as patent rights) and the right to use in future works.-
dc.subject.lcshEndothelins-
dc.subject.lcshCognition disorders-
dc.titleThe examination of endothelin-1 effects on vascular-neurodegenerative pathways contributing to cognitive impairment-
dc.typePG_Thesis-
dc.identifier.hkulb5177340-
dc.description.thesisnameMaster of Philosophy-
dc.description.thesislevelMaster-
dc.description.thesisdisciplinePsychiatry-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.5353/th_b5177340-

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