Differential assembly of human tau isoforms in the presence of arachidonic acid.
Six tau isoforms arise from the alternative splicing of a single gene in humans. Insoluble, filamentous deposits of tau protein occur in a number of neurodegenerative diseases, and in some of these diseases, the deposition of polymers enriched in certain tau isoforms has been documented. Because of these findings, we have undertaken studies on the efficacy of fatty acid-induced polymerization of the individual tau isoforms found in the adult human CNS. The polymerization of each tau isoform in the presence of two concentrations of arachidonic acid indicated that isoforms lacking N-terminal exons e2 and e3 formed small, globular oligomers that did not go on to elongate into straight (SF) or paired helical (PHF) filaments under our buffer conditions. The polymerization of all isoforms containing e2 or e2 and e3 occurred readily at a high arachidonic acid concentration. Conversely, at a lower arachidonic acid concentration, only tau isoforms containing four microtubule binding repeats assembled well. Under all buffer conditions employed, filaments formed from three of the isoforms containing e2 and e3 resembled SFs in morphology but began to form PHF-like structures following extended incubation at 37 degrees C. These results indicate that polymerization of the intact tau molecule may be facilitated by e2 and e3. Moreover, tau isoforms containing three versus four microtubule binding repeats display different assembly properties depending on the solvent conditions employed.
King
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Department of Cell and Molecular Biology and Cognitive Neurology and Alzheimer's Disease Center, Northwestern University Medical School, Chicago, Illinois 60611, USA. mking@nwu.edu
Gamblin
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TC
Kuret
J
J
Binder
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D008841:Actin Cytoskeleton / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D000328:Adult; D016718:Arachidonic Acid / Q000494:pharmacology*; D002460:Cell Line; D006801:Humans; D066298:In Vitro Techniques; D007536:Isomerism; D008854:Microscopy, Electron; D016874:Neurofibrillary Tangles / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D016875:tau Proteins / Q000737:chemistry* / Q000378:metabolism* / Q000648:ultrastructure
D016875:tau Proteins; D016718:Arachidonic Acid