Abstract
In Alzheimer's disease, microtubule-associated protein tau is hyperphosphorylated by an unknown mechanism and is aggregated into paired helical filaments. Hyperphosphorylation causes loss of tau function, microtubule instability, and neurodegeneration. Glycogen synthase kinase-3beta (GSK3beta) has been implicated in the phosphorylation of tau in normal and Alzheimer's disease brain. The molecular mechanism of GSK3beta-tau interaction has not been clarified. In this study, we find that when microtubules are disassembled, microtubule-associated GSK3beta dissociates from microtubules. From a gel filtration column, the dissociated GSK3beta elutes as an approximately 400-kDa complex. When fractions containing the approximately 400-kDa complex are chromatographed through an anti-GSK3beta immunoaffinity column, tau co-elutes with GSK3beta. From fractions containing the approximately 400-kDa complex, both tau and GSK3beta co-immunoprecipitate with each other. GSK3beta binds to nonphosphorylated tau, and the GSK3beta-binding region is located within the N-terminal projection domain of tau. In vitro, GSK3beta associates with microtubules only in the presence of tau. From brain extract, approximately 6-fold more GSK3beta co-immunoprecipitates with tau than GSK3alpha. These data indicate that, in brain, GSK3beta is bound to tau within a approximately 400-kDa microtubule-associated complex, and GSK3beta associates with microtubules via tau.
Highlights
In Alzheimer’s disease (AD),1 microtubule-associated protein tau becomes hyperphosphorylated and aggregates into paired helical filaments (PHFs)
Tubulin was recovered within the flowthrough fractions, and column-bound GSK3 was eluted with a NaCl gradient
When the MAP fraction was subjected to an FPLC gel filtration analysis, GSK3 eluted as a ϳ400-kDa complex
Summary
In Alzheimer’s disease (AD), microtubule-associated protein tau becomes hyperphosphorylated and aggregates into paired helical filaments (PHFs) (reviewed in Refs. 1 and 2). GSK3 is widely expressed in various mammalian tissues and cell lines [11] It phosphorylates many proteins such as glycogen synthase, eukaryotic initiation factor 2B, ATP citrate lyase, the regulatory subunit of PKA, c-Jun, c-Myc, cAMPresponse element-binding protein, inhibitor-2, -catenin, neurofilaments, synapsin, and adenomatous polyposi coli gene product [12,13,14,15,16,17,18,19,20,21,22] and regulates glycogen metabolism, lipid synthesis, cytoskeletal arrangement, gene expression, apoptosis, and cell fate specification GSK3 phosphorylates tau on Ser199, Thr231, Ser396, and Ser413 (numbered according to the longest tau isoform) [23], and these sites are phosphorylated in PHF-tau [9]. The GSK3 inhibitor LiCl suppresses tau phosphorylation, enhances tau-microtubule binding, and promotes micro-
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
