Ca2+ and Mg2+ selectively induce aggregates of PHF-tau but not normal human tau.
The molecular mechanism of pathological aggregation of microtubule-associated protein tau during neurodegeneration is unclear. In the present study, the in vitro effect of various metal ions on the aggregation of tau was examined using paired helical filament tau (PHF-tau) obtained from corticobasal degeneration (CBD) and Alzheimer's disease (AD) brains as well as normal human tau proteins isolated from fetal and adult brains and a recombinant system. Among the metal ions tested, Ca2+ and Mg2+ effectively induced formation of approximately 340 kD aggregates of PHF-tau but not normal tau proteins as determined by sodium dodecyl sulfate (SDS)-polyacrylamide gel electrophoresis and immunoblotting. Al3+ and Fe2+ precipitated both PHF-tau and normal tau protein as SDS-insoluble pellets. The other metal ions examined (Cu2+, Zn2+, and Li+) were inactive and caused neither aggregation nor precipitation of any tau protein. Intermixing experiments using PHF-tau and various normal tau preparations showed that the 340-kD aggregates induced by Ca2+ contained PHF-tau but not normal tau regardless whether unmodified (recombinant) or highly phosphorylated (fetal brain) tau proteins were used. The present results suggest that post-translational modifications other than the fetal-type phosphorylation are required for Ca2+- and Mg2+-dependent aggregation of PHF-tau and that the regional elevation of these ions may trigger pathological deposition of PHF-tau in certain neurodegenerative disorders.
Yang
L S
LS
Department of Pathology, Albert Einstein College of Medicine, Bronx, New York 10461, USA. lyang@aecom.yu.edu
Ksiezak-Reding
H
H
D000255:Adenosine Triphosphate / Q000378:metabolism; D000368:Aged; D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D001921:Brain / Q000196:embryology; D001923:Brain Chemistry; D002118:Calcium / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D002413:Cations, Divalent / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D006801:Humans; D015151:Immunoblotting; D008274:Magnesium / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D010766:Phosphorylation; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D016875:tau Proteins / Q000737:chemistry / Q000378:metabolism*
D002413:Cations, Divalent; D011994:Recombinant Proteins; D016875:tau Proteins; D000255:Adenosine Triphosphate; D008274:Magnesium; D002118:Calcium