Alzheimer¡¦s disease (AD) is a neurodegenerative disorder characterized by progressive deterioration of cognitive functions and the presence of intracellular neurofibrillary tangles (NFT) and extraneuronal senile plaques (SP). The major component of NFT is the hyperphosphorylated microtubules-associated protein tau. SP is consistent of extracellular deposition of £]-amyloid (A£]), mainly A£]1-42 peptide (A£]42). Given the need of tools for early and accurate diagnosis and prediction of disease progression and monitoring the efficacy of therapeutic agents for AD, development of cerebrospinal fluid (CSF) biomarkers have become a rapidly growing research field. In our study, patients with AD (n=28), non-AD dementia (n=16), other neurological disorder (OND, n=14) and healthy controls (HC, n=21) were included. Our results revealed that AD patients have significant higher CSF total tau (t-tau) and lower A£]42 levels than HC and OND groups. There is no significant difference of both CSF t-tau and A£]42 levels between AD and non-AD dementia groups. These results suggest that both CSF t-tau and A£]42 are good biomarkers for distinguishing AD from non-dementia control subjects but demonstrate less discriminating power in differentiating AD from non-AD dementia. Moreover, our results show only CSF t-tau level but not A£]42 has an inverse correlation with the score of short-term memory patients with AD (spearman: r = -0.444; p=0.018). These data indicate the higher CSF t-tau level is associated with much NFT pathology and more severe impairment of short-term memory in AD patients. In the study of the moleacular mechanism of tau¡¦s hyperphosphorylation by glycogen synthase kinase 3b (GSK3b), we show that the T231 is the primary phosphorylation site for GSK3b and the tau227-237 (AVVRTPPKSPS) derived from tau containing T231P232 motif is identified as the GSK3b binding site with high affinity of a Kd value 0.82 ¡Ó 0.16 mM. Our results suggest that direct binding and phosphorylation of T231P232 motif by GSK3b induces conformational change of tau and consequentially alters the inhibitory activity of its N-terminus that allows the sequential phosphorylation of C-terminus of tau by GSK3b. Furthermore, hyperphosphorylation reduces tau¡¦s ability to promote tubulin assembly and to form bundles in N18 cells. T231A mutant completely abolishes tau phosphorylation by GSK3b and retains the ability to promote tubulin polymerization and bundle formation. Taken together, these results suggest that phosphorylation of T231 by GSK3b may play an important role in tau¡¦s hyperphosphorylation and functional regulation.
| Identifer | oai:union.ndltd.org:NSYSU/oai:NSYSU:etd-0622109-103048 |
| Date | 22 June 2009 |
| Creators | Lin, Yuh-te |
| Contributors | Cheng, Jiin-Tsueg, Hong, Yi-Ren, Hsiao, Michael, Lu, Pei-Jung, Cho, Chung-Lung, Lo, Yuk-Keung |
| Publisher | NSYSU |
| Source Sets | NSYSU Electronic Thesis and Dissertation Archive |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.lib.nsysu.edu.tw/ETD-db/ETD-search/view_etd?URN=etd-0622109-103048 |
| Rights | not_available, Copyright information available at source archive |
Page generated in 0.0016 seconds