Thesis (Ph. D.)--University of Hong Kong, 2010. / Includes bibliographical references (p. 256-292). Also available in print.

Thesis (Ph. D.)--Case Western Reserve University, 2004. / [School of Medicine] Department of Neurosciences. Includes bibliographical references. Available online via OhioLINK's ETD Center.

Title from PDF of title page (University of Missouri--Columbia, viewed on Feb 25, 2010). The entire thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file; a non-technical public abstract appears in the public.pdf file. Dissertation advisor: Dr. Anand Chandrasekhar. Vita. Includes bibliographical references.

Thesis (Ph. D.)--Hong Kong University of Science and Technology, 2004. / Includes bibliographical references (leaves 134-172). Also available in electronic version. Access restricted to campus users.

Thesis (M.S.)--West Virginia University, 2001. / Title from document title page. Document formatted into pages; contains vii, 79 p. : ill. (some col.). Vita. Includes abstract. Includes bibliographical references (p. 70-78).

Thesis (M. Sc.)--York University, 2001. Graduate Programme in Kinesiology and Health Science. / Typescript. Includes bibliographical references. Also available on the Internet. MODE OF ACCESS via web browser by entering the following URL: http://wwwlib.umi.com/cr/yorku/fullcit?pMQ71585.

Alzheimer’s disease (AD) is the most frequent neurodegenerative disorder which is characterized by impaired mental functions such as memory, language, perception, behavior and personality, as well as cognitive skills. The molecular mechanisms underlying this disease is still largely unknown, but numerous evidence emerge to support a cell cycle hypothesis which implicates the deregulation of cell cycle proteins as key mediators of neuronal dysfunction and loss in AD brains. One of these signals in Aβ-induced neuronal death model is Cdk/Rb/E2F pathway, where Aβ insult evokes activation of Cdk4/6, which subsequently phosphorylates pRb protein, resulting in activation of E2F transcription factors. However, the mechanism(s) by which Cdk/Rb/E2F mediates neuronal death remains elusive. Therefore, the goal of this project is to characterize the downstream events of cell cycle pathway, which include the involvement of transcription factors c-Myb, Pax6 and Patz1 in Aβ-induced neuronal death signaling. In this study, we showed that Pax6 is a direct target gene for Both E2F1 and c-Myb. Both Pax6 and c-Myb are up-regulated by Aβ insults in cultured cortical neurons. And with E2F1 silencing by siRNA, Aβ-induced Pax6 and c-Myb expression is blocked, suggesting E2F1 is responsible for their elevation. Importantly, siRNA-mediated downregulation of either c-Myb or Pax6 protects neurons from death evoked by Aβ peptide, suggesting they are proapoptotic proteins, delivering death signals sent from upstream E2F1. Next, though ChIP assay, we identified two target genes for Pax6. One is Patz1, another transcription factor that is Aβ-induced pro-apoptotic protein. The other one is GSK3β, which is a pathogenic kinase involved in Tau protein hyperphosphorylation and NFT formation. In conclusion, this dissertation shows that cell cycle regulators Cdk/Rb/E2F modulate neuronal death signals by activating downstream transcription factors c-Myb and Pax6, further upregulating GSK3β. We provided evidence suggesting that Aβ induced neurotoxicity leads to Tau hyperphosphorylation through a mechanism involving cell cycle activation and subsequent activation of c-Myb/Pax6/GSK3β. In brief, in the present study, we delineate a transcriptional cascade downstream of cell cycle pathway leads to neuronal apoptosis as well as Tau/NFT pathology. The characterization of this novel pathway lends support for development of new therapeutic agents and for better experimental models for AD. Lastly, the cascade between cell cycle activation and tauopathy in Aβ-induced neuronal death needs to be further researched in the future. / HKU 3 Minute Thesis Award, Champion (2011) / published_or_final_version / Biochemistry / Doctoral / Doctor of Philosophy

published_or_final_version / Physiology / Master / Master of Philosophy

published_or_final_version / Electrical and Electronic Engineering / Doctoral / Doctor of Philosophy

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