Aggregation of tau protein by aluminum.
Aluminum has been detected in Alzheimer neurofibrillary tangles, but the significance of its presence is unknown. The principal component of tangles is the paired helical filament (PHF), comprised of tau protein. We investigated whether aluminum could induce tau protein to form filaments or aggregate. When 10 microM bovine tau or non-phosphorylated recombinant human tau was combined with 400 microM or more aluminum, tau protein appeared to aggregate, observed as a dose-dependent decrease in electrophoretic mobility on SDS-PAGE. Tau appeared as a smear above the region of the expected tau bands and, at higher aluminum doses, failed to enter the gel. A tau fragment encompassing the microtubule binding domains did not show decreased mobility in the presence of aluminum, but did form aggregates that failed to electrophorese. However no fibrillar structures were observed in the aluminum-treated tau samples when observed by electron microscopy. The effect of aluminum on tau mobility was reversed by incubating with 1 mM deferoxamine. In contrast, the morphology of PHF fibrils was unaffected by deferoxamine treatment and the characteristic abnormal mobility of PHF-tau was not reduced by deferoxamine. This suggests that aluminum is not, by itself, a significant factor in maintaining the assembly of PHF-tau as fibrils or in its abnormal mobility on SDS gels. Aluminum treatment of 3T3 fibroblasts transfected with human tau resulted in toxicity, but did not change tau expression levels or induce tau aggregation. In conclusion, aluminum appears to induce isolated tau protein to aggregate in a phosphate-independent way, without the formation of fibrils.(ABSTRACT TRUNCATED AT 250 WORDS)
Scott
C W
CW
Pharmacology Department, ICI Americas, Wilmington, DE 19897.
Fieles
A
A
Sygowski
L A
LA
Caputo
C B
CB
D016475:3T3 Cells; D000535:Aluminum / Q000494:pharmacology*; D000818:Animals; D002417:Cattle; D003676:Deferoxamine / Q000494:pharmacology; D004591:Electrophoresis, Polyacrylamide Gel; D006801:Humans; D051379:Mice; D008854:Microscopy, Electron; D016900:Neurofilament Proteins / Q000187:drug effects*; D010766:Phosphorylation; D011994:Recombinant Proteins / Q000187:drug effects; D014162:Transfection; D016875:tau Proteins / Q000187:drug effects*
D016900:Neurofilament Proteins; D011994:Recombinant Proteins; D016875:tau Proteins; D000535:Aluminum; D003676:Deferoxamine