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postgraduate thesis: Elucidating the mechanisms of cytoskeletal pathologies in experimental Alzheimer's disease and major depression models

TitleElucidating the mechanisms of cytoskeletal pathologies in experimental Alzheimer's disease and major depression models
Authors
Issue Date2014
PublisherThe University of Hong Kong (Pokfulam, Hong Kong)
Citation
Wong, T. G. [黃芷軒]. (2014). Elucidating the mechanisms of cytoskeletal pathologies in experimental Alzheimer's disease and major depression models. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. Retrieved from http://dx.doi.org/10.5353/th_b5558947
AbstractMajor depressive disorder (MDD) is a devastating psychiatric disorder that affects more than 300 million people worldwide. Current treatment relies on antidepressants and psychotherapy, but fails in those who are treatment-resistant. MDD is recognized as a risk factor of Alzheimer’s disease (AD) and their comorbidity is known as depression in AD (dAD). The prevalence of AD is also vastly increasing. Difficulties in early diagnosis and limited treatment render AD to be a great burden to the healthcare system. Patients of dAD experience more severe symptoms and lower quality of life. Investigation of the common pathological features between MDD and AD will help elucidate mechanisms that lead to common neurodegenerative pathways. Dendritic regression and synaptic loss are commonly observed in MDD and AD. Cytoskeletal dysfunction including microtubule and actin plays a role in many psychiatric disorders. Microtubule and actin function and morphology are governed by specific modifications and signaling pathways. Alteration in these processes may affect their function. The roles of microtubule and actin in MDD and AD as a common pathological feature will be investigated. Primary culture of hippocampal neurons from Sprague Dawley rats was exposed to corticosterone (CORT) or oligomeric amyloid β (Aβ1-42) for 24 or 48 hr to induce in vitro models of MDD and AD, respectively. Neurons were grown to day 14 or 21. This study demonstrated the effects of CORT or Aβ1-42 on microtubule and actin. Results revealed reduction in microtubule stability through unevenly distributed immunoreactivity of microtubule-associated protein 2 and decreased acetylated tubulin. Alteration in the tyrosinated to detyrosinated tubulin ratio may be a contributing factor to decreased colocalization with plus end binding protein 3. On the other hand, decrease in post-synaptic density 95 immunoreactivity and level of β-actin postulated synaptic changes caused by exposure to CORT or Aβ1-42. Actin rods were apparent in neurons exposed to CORT or Aβ1-42, suggesting a possible involvement of oxidative stress. Signaling molecules cofilin and LIM kinase responsible for rods formation were significantly increased. More importantly, this study demonstrated the impact of microtubule stability on the integrity of actin filament. Treatment with taxol prior to exposure to CORT or Aβ1-42 prevented changes caused by the two treatments. In conclusion, this study showed the effects of CORT or Aβ1-42 on microtubule and actin filaments. The dysfunction of these cytoskeletal proteins is a common pathological feature of MDD and AD. Furthermore, the importance of microtubule stability in maintaining actin integrity has been established. This study provides knowledge in understanding the mechanism of neurodegeneration in MDD and AD. Finally, it gives insight to potential therapeutic pathways.
DegreeDoctor of Philosophy
SubjectAlzheimer's disease
Depression, Mental
Dept/ProgramPsychiatry
Persistent Identifierhttp://hdl.handle.net/10722/224405

 

DC FieldValueLanguage
dc.contributor.authorWong, Tsz-hin, Ginger-
dc.contributor.author黃芷軒-
dc.date.accessioned2016-04-01T23:15:40Z-
dc.date.available2016-04-01T23:15:40Z-
dc.date.issued2014-
dc.identifier.citationWong, T. G. [黃芷軒]. (2014). Elucidating the mechanisms of cytoskeletal pathologies in experimental Alzheimer's disease and major depression models. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. Retrieved from http://dx.doi.org/10.5353/th_b5558947-
dc.identifier.urihttp://hdl.handle.net/10722/224405-
dc.description.abstractMajor depressive disorder (MDD) is a devastating psychiatric disorder that affects more than 300 million people worldwide. Current treatment relies on antidepressants and psychotherapy, but fails in those who are treatment-resistant. MDD is recognized as a risk factor of Alzheimer’s disease (AD) and their comorbidity is known as depression in AD (dAD). The prevalence of AD is also vastly increasing. Difficulties in early diagnosis and limited treatment render AD to be a great burden to the healthcare system. Patients of dAD experience more severe symptoms and lower quality of life. Investigation of the common pathological features between MDD and AD will help elucidate mechanisms that lead to common neurodegenerative pathways. Dendritic regression and synaptic loss are commonly observed in MDD and AD. Cytoskeletal dysfunction including microtubule and actin plays a role in many psychiatric disorders. Microtubule and actin function and morphology are governed by specific modifications and signaling pathways. Alteration in these processes may affect their function. The roles of microtubule and actin in MDD and AD as a common pathological feature will be investigated. Primary culture of hippocampal neurons from Sprague Dawley rats was exposed to corticosterone (CORT) or oligomeric amyloid β (Aβ1-42) for 24 or 48 hr to induce in vitro models of MDD and AD, respectively. Neurons were grown to day 14 or 21. This study demonstrated the effects of CORT or Aβ1-42 on microtubule and actin. Results revealed reduction in microtubule stability through unevenly distributed immunoreactivity of microtubule-associated protein 2 and decreased acetylated tubulin. Alteration in the tyrosinated to detyrosinated tubulin ratio may be a contributing factor to decreased colocalization with plus end binding protein 3. On the other hand, decrease in post-synaptic density 95 immunoreactivity and level of β-actin postulated synaptic changes caused by exposure to CORT or Aβ1-42. Actin rods were apparent in neurons exposed to CORT or Aβ1-42, suggesting a possible involvement of oxidative stress. Signaling molecules cofilin and LIM kinase responsible for rods formation were significantly increased. More importantly, this study demonstrated the impact of microtubule stability on the integrity of actin filament. Treatment with taxol prior to exposure to CORT or Aβ1-42 prevented changes caused by the two treatments. In conclusion, this study showed the effects of CORT or Aβ1-42 on microtubule and actin filaments. The dysfunction of these cytoskeletal proteins is a common pathological feature of MDD and AD. Furthermore, the importance of microtubule stability in maintaining actin integrity has been established. This study provides knowledge in understanding the mechanism of neurodegeneration in MDD and AD. Finally, it gives insight to potential therapeutic pathways.-
dc.languageeng-
dc.publisherThe University of Hong Kong (Pokfulam, Hong Kong)-
dc.relation.ispartofHKU Theses Online (HKUTO)-
dc.rightsThe author retains all proprietary rights, (such as patent rights) and the right to use in future works.-
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License-
dc.subject.lcshAlzheimer's disease-
dc.subject.lcshDepression, Mental-
dc.titleElucidating the mechanisms of cytoskeletal pathologies in experimental Alzheimer's disease and major depression models-
dc.typePG_Thesis-
dc.identifier.hkulb5558947-
dc.description.thesisnameDoctor of Philosophy-
dc.description.thesislevelDoctoral-
dc.description.thesisdisciplinePsychiatry-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.5353/th_b5558947-

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