碩士 / 國立陽明大學 / 生物藥學研究所 / 97 / Alzheimer’s disease (AD), the most common neurodegenerative dementia, is neuropathologically characterized by the extracellular Amyloid ���n�vA���w�npeptides accumlation forming a senile plaque and the intracellular accumulation of neurofibrillary tangles composed of hyperphosphorylated tau. Amyloid plaques were considered as the prime pathogenic driver of neurodegeneration in AD. However, many studies suggested that amyloid plaques alone may not be able to explain the neuron loss and cognitive ability decline in AD. Therefore, both Aβand tau were equally important on AD pathogenesis, and tau phosphorylation may be induced by Aβ, microglia, excitotoxicity and oxidative stress. The aim of this thesis is to investigate the effects of tau hyperphosphorylation mediated by Aβ, microglia, excitotoxicity and oxidative stress. Futhermore, the mechanism of Aβ- and microglia– mediated tau phosphorylation was also investigated. We found that Aβ25-35 fibril and Aβ1-42 oligomer significantly increased tau phosphorylation at Ser404, but not at Ser413, Ser214 and Thr212 in cortical neurons, Aβ1-42 fibril and oligomer significantly increased tau phosphorylation at Ser404 in the co-culture of cortical neuons with microglia-derived cell line (BV2). The results suggest that Aβ may induce neuronal tau phosphorylation directly or indirectly through microglia activation by Aβ. In respect of tau phosphorylation mediated by excitotoxicity and oxidative stress, cortical neurons were treated with N-methyl-D-asparate (NMDA) and H2O2, respectively. NMDA significantly increased tau phosphorylation of 72-kDa band at Ser404, but not at Ser413 and Ser214. Nevertheless, tau phosphorylation Thr212 decreased in a concentration and time dependent manner. On the other hand, H2O2 failed to induce tau phosphoryaltion at Ser404 in cortical neurons. Regarding the mechanism of tau phosphoryaltion, GSK- 3�� is one of the tau-protein kinases. We found that Aβ1-42 oligomer decreased the phosphorylation of GSK-3���nat Ser9 (the inactive from of GSK-3��). On the contrary, the GSK-3�� activation induced by Aβ1-42 oligomer and fibril were not observed in the co-culture of cortical neurons and BV2 cells.
| Identifer | oai:union.ndltd.org:TW/097YM005603006 |
| Date | January 2009 |
| Creators | Yu-Chi Chen, 陳宇綮 |
| Contributors | Young-Ji Shiao, 蕭永基 |
| Source Sets | National Digital Library of Theses and Dissertations in Taiwan |
| Language | zh-TW |
| Detected Language | English |
| Type | 學位論文 ; thesis |
| Format | 56 |
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