Differential Assembly of Human Tau Isoforms in the Presence of Arachidonic Acid

Abstract

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 acidinduced 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°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. Key Words: Tau-Tau isoforms-Arachidonic acid.

Filamentous Tau in Oligodendrocytes and Astrocytes of Transgenic Mice Expressing the Human Tau Isoform with the P301L Mutation

“…The significance of the two N-terminal inserts encoded by exons 2 and 3 is currently unknown; however, in vitro studies have shown that the 4R2N isoform of tau assembles into filaments faster than 4R0N. 46 In summary, the present study demonstrates filamentous tau lesions in astrocytes and oligodendrocytes of transgenic mice expressing P301L mutant human tau, a model also characterized by neurofibrillary tangles, neuronal loss and progressive amyotrophy. The tau filaments formed argyrophilic inclusions in oligodendrocytes, but not in astrocytes.…”

Tau Isoform Composition Influences Rate and Extent of Filament Formation

“…Materials-Recombinant His-tagged human Tau isoforms were prepared as described previously (23,30). Aggregation inducer Thiazine red (Chemical Abstract Service registry no.…”

“…In contrast, both Nand C-terminal inserts that arise from alternative splicing have been reported to modulate Tau aggregation propensity in the presence of heparin and anionic surfactant aggregation inducers (20 -24). Under these conditions, which leverage a heterogeneous nucleation mechanism (25), isoform aggregation propensity is differentially influenced by Tau:inducer ratios (22)(23)(24). As a result, the reported contribution of segments encoded by alternatively spliced exons to aggregation propensity has been inconsistent.…”

Anionic Micelles and Vesicles Induce Tau Fibrillization in Vitro

“…htau40 was used because of ease and yield of preparation and because the presence of the tag does not significantly change the rate or extent of AAinduced tau fibrillization (26). Nonionic detergents tested included the polyoxyethylenes Triton X-100 (data not shown), Tween 20, C 8 E 4 , C 10 E 6 , C 10 E 8 , C 12 E 23 , and C 14 E 6 .…”