Neuropathological hallmarks of Alzheimer's disease are extracellular senile plaques and intracellular neurofibrillary lesions. The neurofibrillary lesions mainly consist of the hyperphosphorylated microtubule-associated protein Tau predominantly expressed in the axon of CNS neurons. Hyperphosphorylation of Tau negatively affects its binding to tubulin and decreases the capacity to promote microtubule assembly. Among a number of proline-directed kinases capable of phosphorylating paired helical filament-Tau, glycogen synthase kinase 3b (GSK3b) was first identified as a Tau protein kinase I and has been demonstrated to phosphorylate Tau both in vivo and in vitro. However, the phosphorylation mechanism of Tau by GSK3b remained unclear. In this study, 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 ± 0.16 lmol/L. 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 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. Keywords: Alzheimer's disease, glycogen synthase kinase 3b, hyperphosphorylation, Tau, Thr231. J. Neurochem. (2007) 103, 802-813. A diagnosis of Alzheimer's disease (AD) is made when a patient exhibits clinical evidence of progressive dementia and when a post-mortem examination of brain reveals the characteristic neuropathology consisting of extracellular senile plaques and intracellular neurofibrillary lesions (Goedert and Spillantini 2006). The neurofibrillary lesions mainly consist of the hyperphosphorylated microtubule (MT)-associated protein Tau (Avila 2006). Tau is a family of MTassociated proteins that are produced by alternative mRNA splicing of a single gene as six isoforms and express predominantly within neurites and axons in adult brain. The largest Tau found in the brain containing 441 amino acids contains two N-terminal inserts and four MT-binding repeats. However, the smallest isoform has no N-terminal insert and has three MT-binding repeats instead (Buee et al. 2000;Avila 2006). Interestingly, 4R-tau was easily phosphorylated by brain protein kinases and aggregated into filaments Received January 31, 2007; revised manuscript received April 25, 2007; accepted June 13, 2007. Address correspondence and reprint requests to Pei-Jung Lu, PhD, Department of Medical Education and Research, Kaohsiung Veterans General Hospital 386 Ta-Chung 1st Rd., Kaoh...
Given the need for tools for early and accurate diagnosis, prediction of disease progression, and monitoring efficacy of therapeutic agents for AD, the study of cerebrospinal fluid (CSF) biomarkers has become a rapidly growing field of research. Several studies have reported conflicting data regarding the relationships between CSF biomarkers and dementia severity. In this study, we have focused on the identification of CSF biomarkers and their correlations with the impairment of different cognitive domains measured using the Cognitive Abilities Screening Instrument (CASI). Patients with AD (n=28), non-AD dementia (n=16), other neurological disorders (OND, n=14), and healthy controls (HC, n=21) were enrolled. Our results revealed significantly higher CSF total tau (t-tau) and lower amyloid-beta(42) levels in AD patients compared with those in HC and OND groups. Moreover, our data show that CSF t-tau levels, but not Abeta(42) levels, have an inverse correlation with the score of short-term memory in CASI for patients with AD (Spearman: r=-0.444; p=0.018). This data might indicate that the higher CSF t-tau level is associated with more NFT pathology and more severe impairment of short-term memory in AD patients.
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