Abstract
Hyperphosphorylated microtubule-associated protein tau is the major proteinaceous component of the paired helical and straight filaments which constitute a defining neuropathological characteristic of Alzheimer's disease and a number of other neurodegenerative disorders. We have recently shown that full-length recombinant tau assembles into Alzheimer-like filaments upon incubation with heparin. Heparin also promotes phosphorylation of tau by a number of protein kinases, prevents tau from binding to taxol-stabilized microtubules, and produces rapid disassembly of microtubules assembled from tau and tubulin. Here, we have used the above parameters to study the interactions between tau protein and a number of naturally occurring and synthetic glycosaminoglycans. We show that the magnitude of the glycosaminoglycan effects is proportional to their degree of sulfation. Thus, the strongly sulfated glycosaminoglycans dextran sulfate, pentosan polysulfate, and heparin were the most potent, whereas the non-sulfated dextran and hyaluronic acid were without effect. The moderately sulfated glycosaminoglycans heparan sulfate, chondroitin sulfate, and dermatan sulfate had intermediate effects, whereas keratan sulfate had little or no effect. These in vitro interactions between tau protein and sulfated glycosaminoglycans reproduced the known characteristics of paired helical filament-tau from Alzheimer's disease brain. Sulfated glycosaminoglycans are present in nerve cells in Alzheimer's disease brain in the early stages of neurofibrillary degeneration, suggesting that their interactions with tau may constitute a central event in the development of the neuronal pathology of Alzheimer's disease.
Highlights
Hyperphosphorylated microtubule-associated protein tau is the major proteinaceous component of the paired helical and straight filaments which constitute a defining neuropathological characteristic of Alzheimer’s disease and a number of other neurodegenerative disorders
We show that the phosphorylation of tau by mitogen-activated protein (MAP) kinase, neuronal cdc2-like kinase (NCLK), and glycogen synthase kinase-3 (GSK3) is markedly stimulated in the presence of heparin, at heparin concentrations lower than those required for tau filament formation
Phosphorylation of tau by NCLK in the presence of heparin produced the epitopes of phosphorylation-dependent anti-tau antibodies which recognize (S/T)P sites in tau, as shown in Fig. 2 for antibody AT8 which recognizes tau phosphorylated at Ser-202 and Thr-205 [8]
Summary
This table has been adapted from Ref. 57. not by dextran and hyaluronic acid, with the magnitude of stimulation of tau phosphorylation being proportional to the degree of glycosaminoglycan sulfation. Not by dextran and hyaluronic acid, with the magnitude of stimulation of tau phosphorylation being proportional to the degree of glycosaminoglycan sulfation. Incubation of tau with tRNA led to the formation of filaments, in confirmation of a recent report [33]. These results raise the possibility that an interaction between tau protein and negatively charged polymers with a sugar backbone, as found in sulfated glycosaminoglycans and nucleic acids, results in a conformational change in tau that induces polymerization of tau molecules via the microtubulebinding repeats of individual tau molecules, resulting in the formation of filaments like those present in Alzheimer’s disease and other neurodegenerative disorders
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