Differential assembly of human tau isoforms in the presence of arachidonicacid

Six tau isoforms arise from the alternative splicing of a single gene in hu mans. Insoluble, filamentous deposits of tau protein occur in a number of n euro-degenerative diseases, and in some of these diseases, the deposition o f polymers enriched in certain tau isoforms has been documented. Because of these findings, we have undertaken studies on the efficacy of fatty acid-i nduced polymerization of the individual tau isoforms found in the adult hum an CNS. The polymerization of each tau isoform in the presence of two conce ntrations of arachidonic acid indicated that isoforms lacking N-terminal ex ons e2 and e3 formed smalt, globular oligomers that did not go on to elonga te into straight (SF) or paired helical (PHF) filaments under our buffer co nditions. The polymerization of all isoforms containing e2 or e2 and e3 occ urred readily at a high arachidonic acid concentration. Conversely, at a lo wer arachidonic acid concentration, only tau isoforms containing four micro tubule binding repeats assembled well. Under all buffer conditions employed , filaments formed from three of the isoforms containing e2 and e3 resemble d SFs in morphology but began to form PHF-like structures following extende d incubation at 37 degrees C. These results indicate that polymerization of the intact tau molecule may be facilitated by e2 and e3. Moreover, tau iso forms containing three versus four microtubule binding repeats display diff erent assembly properties depending on the solvent conditions employed.