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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 state^3–8. Hyperphosphorylation of tau results in its inability to bind to microtubules^9,10 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 …