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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

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Brain deposition of the $ beta$-amyloid protein is an early marker of Alzheimer's disease (AD). AD is a neurodegenerative disorder characterized by learning and memory impairments. Here, mice (B6C3, 8 and 20 months old) transgenic for a human $ beta$-amyloid fragment were compared to normal litter mates in spatial and non-spatial learning tasks in the Morris water maze, according to standard procedures. Four measures of learning and performance were analyzed statistically: latency, total distance swam, mean distance to a platform, and number of trials correct in reaching a platform. Transgenic mice were impaired relative to their litter mates in spatial learning and performed better in the non-spatial task than in the spatial task in the first three measures. An age effect for transgenics was observed in the total distance measure. The results suggest that expression of the human $ beta$-amyloid protein may produce a selective learning deficit in mice.

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The experiment tested the hypothesis that 192 IgG-saporin lesions of the nucleus basalis magnocellularis (NBM) in rats would impair performance in a biconditional visual discrimination task, which requires configural association learning. Experiment used 22 male Long-Evan rats (Harlan Sprague-Dawley). Behavioral testing was conducted in two identical T-mazes. Rats were randomly assigned to either a bilateral 192 IgG-saporin lesion group (n = 10) or to a control group (n = 12). Results support the hypothesis that NBM is critically involved in configural but not simple association learning and suggest that NBM may be involved more generally in cognitive flexibility.