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Assembly of microtubule-associated protein tau into Alzheimer-like filaments induced by sulphated glycosaminoglycans

Abstract

THE paired helical filament (PHF) is the major component of the neurofibrillary deposits that form a defining neuropathological characteristic of Alzheimer's disease (reviewed in refs 1,2). PHFs are composed of micro tubule-associated protein tau, in a hyper-phosphorylated state3–8. Hyperphosphorylation of tau results in its inability to bind to microtubules9,10 and is believed to precede PHF assembly11. However, it is unclear whether hyperphosphor-ylation of tau is either necessary or sufficient for PHF formation. Here we show that non-phosphorylated recombinant tau iso-forms with three microtubule-binding repeats form paired helical-like filaments under physiological conditions in vitro, when incubated with sulphated glycosaminoglycans such as heparin or heparan sulphate. Furthermore, heparin prevents tau from binding to microtubules and promotes microtubule disassembly. Finally, we show that heparan sulphate and hyperphosphorylated tau coexist in nerve cells of the Alzheimer's disease brain at the earliest known stages of neurofibrillary pathology. These findings, with previous studies which show that heparin stimulates tau phosphorylation by a number of protein kinases12–14, indicate that sulphated glycosaminoglycans may be a key factor in the formation of the neurofibrillary lesions of Alzheimer's disease.

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Goedert, M., Jakes, R., Spillantini, M. et al. Assembly of microtubule-associated protein tau into Alzheimer-like filaments induced by sulphated glycosaminoglycans. Nature 383, 550–553 (1996). https://doi.org/10.1038/383550a0

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