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
| Identifer | oai:union.ndltd.org:HKU/oai:hub.hku.hk:10722/181605 |
| Date | January 2011 |
| Creators | Zhang, Yalun, 张亚伦 |
| Contributors | Song, Y, Jin, D |
| Publisher | The University of Hong Kong (Pokfulam, Hong Kong) |
| Source Sets | Hong Kong University Theses |
| Language | English |
| Detected Language | English |
| Type | PG_Thesis |
| Source | http://hub.hku.hk/bib/B47331148 |
| Rights | The author retains all proprietary rights, (such as patent rights) and the right to use in future works., Creative Commons: Attribution 3.0 Hong Kong License |
| Relation | HKU Theses Online (HKUTO) |
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