Ca2+ and Mg2+ selectively induce aggregates of PHF-tau but not normal human tau

The molecular mechanism of pathological aggregation of microtubule-associat ed protein tau during neurodegeneration is unclear. In the present study, t he in vitro effect of various metal ions on the aggregation of tau was exam ined using paired helical filament tau (PHF-tau) obtained from corticobasal degeneration (CBD) and Alzheimer's disease (AD) brains as well as normal h uman tau proteins isolated from fetal and adult brains and a recombinant sy stem, Among the metal ions tested, Ca2+ and Mg2+ effectively induced format ion of approximately 340 kD aggregates of PHF-tau but not normal tau protei ns as determined by sodium dodecyl sulfate (SDS)-polyacrylamide gel electro phoresis and immunoblotting. Al3+ and Fe2+ precipitated both PHF-tau and no rmal tan protein as SDS-insoluble pellets, The other metal ions examined (C u2+, Zn2+, and Li+) were inactive and caused neither aggregation nor precip itation of any tau protein, Intermixing experiments using PHF-tau and vario us normal tau preparations showed that the 340-kD) aggregates induced by Ca 2+ contained PHF-tau but not normal tau regardless whether unmodified (reco mbinant) or highly phosphorylated (fetal brain) tau proteins were used. The present results suggest that post-translational modifications other than t he fetal-type phosphorylation are required for Ca2+- and Mg2+-dependent agg regation of PHF-tau and that the regional elevation of these ions may trigg er pathological deposition of PHF-tau in certain neurodegenerative disorder s. (C) 1999 Wiley-Liss, Inc,