MAP-2 Polymerization

MAP-2 POLYMERIZATION & ITS STRUCTURAL RELATENESS TO ALZHEIMERS NEUROFIBRILLARY TANGLES

The microtubule-associated protein tau is widely regarded as the principal component of paired helical filaments comprising Alzheimer's Neurofibrillary Tangles. Tau fragments containing the non-identical repeat region were recently found to polymerize in vitro to form structures resembling PHFs [Schweers et al. (1995). MAP-2, the other major neuronal microtubule-associated protein, is structurally related to tau, but it has not been linked to paired helical filament formation. We now describe the assembly of paired helical filament-like structures from MAP-2 polypeptides containing as few as 100 residues. A dimeric species appears to be involved, and formation of an interchain disulfide may facilitate self-assembly. We also investigated the polymerization properties of embryonic MAP-2c. Except for their microtubule binding regions, MAP-2c and tau are structurally unrelated. Nonetheless, we discovered that full-length MAP-2c forms paired helical filament-like polymers. Polymerized MAP-2 microtubule binding region fragments and polymerized MAP-2c also readily bind thioflavin-S, a dye that binds to paired helical filaments and is frequently used in the histochemical localization of Alzheimer plaque. Our unprecedented finding that MAP-2 microtubule binding region fragments and MAP-2c can assemble into structures resembling paired helical filaments now raises fundamental questions concerning MAP-2's role in the pathobiology of Alzheimer disease.