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Experimental Genetics Group
Alzheimer's disease: Advances in Etiology, Pathogenesis and Therapeutics, 2001;609-620. Spittaels K, Van Den Haute C, Van Dorpe J, Van Leuven F. Experimental Genetics Group, Center for Human Genetics, Flemish Institute for Biotechnology, Katholieke Universiteit Leuven, Leuven, Belgium. Biochemical and structural analysis of the phosphorylation sites of human protein tau of paired helical filaments (PHF) in brain of Alzheimer's disease (AD) patients revealed that many sites consist of serine or threonine residues followed by a proline residue. This obeservation focused attention on proline-dependent kinases (Hasegawa et al., 1992). In the brain of AD patients, NFT were demonstrated to be immunoreactive for glycogen synthase kinase-3ß (GSK-3ß), reffering to a potential association with protein tau (Yamaguchi et al., 1996; Shiurba et al., 1996), and identifying GSK-3ß as one of the possible kinase candidates. In addition, active GSK-3ß is found to accumulate in pre-tangle and tangle-bearing neurons in AD (Pei et al., 1999). Phosphorylation by GSK-3ß of bovine (Ishiguro et al., 1992) and human protein tau (Mandelkow et al., 1992) in cell-free systems, resulted in phosphorylation patterns of protein tau that resemled those of the protein isolated from PHF from AD brain. Further evidence for GSK-3ß as a potential protein tau kinase has been obtained in transfected cells, in which co-transfection of GSK-3ß with protein tau increased its phosphorylation concomitant with loss of prominent bundles of microtubules (Wagner et al., 1996). The involvement of GSK-3ß in the hyperphosphorylation of protein tau, both in cultured neurons and in vivo in brain, was indirectly supported by the finding that lithium, as an inhibitor of GSK-3ß, caused tau dephosphorylation at the sites recognized by antibodies Tau-1 and PHF-1, which are two of the major epitopes typically associated with PHF in AD brain (Muñoz-Montaño et al., 1997; Hong et al., 1997). Despite the wealth of data in vitro, convincing evidence demonstrating the phosphorylation of protein tau by GSK-3ß and the functional repercussions it causes in vivo, is lacking. Solid support for the hypothesis that GSK-3ß is an effective protein tau kinase in vivo, is presented here in single human GSK-3ß[S9A] transgenic mice and in double transgenic mice, additionally expressing human protein tau.  FULL TEXT |
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