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This dissertation, Molecular Mechanisms of Neuronal Death in {221}-amyloid Peptide Toxicity: From Basic Science to Translationalresearch by Man-shan, Yu, 余雯珊, was obtained from The University of Hong Kong (Pokfulam, Hong Kong) and is being sold pursuant to Creative Commons: Attribution 3.0 Hong Kong License. The content of this dissertation has not been altered in any way. We have altered the formatting in order to facilitate the ease of printing and reading of the dissertation. All rights not granted by the above license are retained by the author. Abstract: Abstract of thesis entitled Molecular Mechanisms of Neuronal Death in Beta-Amyloid Peptide Toxicity: From Basic Science to Translational Research submitted by YU Man Shan for the degree of Doctor of Philosophy at The Department of Anatomy, Li Ka Shing Faculty of Medicine, The University of Hong Kong in May 2007 Alzheimer's disease (AD) is an age-related, chronic and fatal neurodegenerative disorder affecting many elders. Global aging population implies the dramatic increase in the number of AD patients. AD is a major health problem as it causes great impacts on individuals, families, health care system and even the whole society. Due to the ineffectiveness of current treatments, there is an urge to investigate the underlying mechanisms of signaling events leading to AD as well as to develop potential neuroprotective agents. One of the pathological hallmarks of AD is the senile plaques in which aggregated beta-amyloid (Aβ) peptides were found in cortex and hippocampus. Aβ peptide-induced apoptosis has been suggested as an important mode of neurodegeneration in AD. Using both cultured neurons and post-mortem AD brain sections, our group has shown that activation of the double-stranded RNA- dependent protein kinase (PKR) and the eukaryotic initiation factor 2 alpha (eIF2α) plays significant roles in Aβ neurotoxicity and AD pathogenesis. We also found that 12+ when neurons are exposed to Aβ peptides, there is an immediate release of Ca 2+ from the ER. According to literature, depletion of Ca from the ER may induce unfolded protein responses (UPR), which may activate PKR-like ER resident kinase 2+ (PERK) and eIF2α. In addition, disturbance of Ca may be an upstream event of PKR activation. These findings led to question whether UPR may also participate in Aβ neurotoxicity. The goal of this study is to further examine the upstream signaling pathway of eIF2α phosphorylation. It is important to identify the pathway because we hypothesized that attenuation of pro-apoptotic pathways can be served as biological targets to be developed for neuroprotective agents. The first part of my study was about the involvement of UPR in extracellular 2+ accumulation of Aβ neurotoxicity. Despite an immediate ER Ca release, Aβ peptides did not induce any UPR signaling including phosphorylation of PERK, alternative cleavage of xbp-1 mRNA and increased gene expression of xbp-1 and gadd153. We could only demonstrate that Aβ peptides triggered mild activation of caspase-7 and -9. My results suggested that extracellular accumulation of Aβ- induced apoptosis is independent of UPR. Based on the current understanding about the molecular mechanisms of Aβ- induced apoptosis, we tried to develop potential treatments for neurodegeneration. Since protein kinases (such as PKR, JNK and Akt) play important roles in Aβ neurotoxicity, it is possible to make use of these signaling pathways as a screening platform to search for neuroprotective agents from different Chinese medicinal herbs. In the second part of my study, I found that aqueous extract from Lycium barbarum can protect neurons against Aβ-induced apoptosis by inhibiting the pro- 2apoptotic PKR and JNK pathways. Meanwhile, polysaccharides from the flowers of Nerium indicum exhibited neuroprotective effects against Aβ neurotoxicity by activating the Akt survival pathway. Finally, I evaluat

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