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Tau Isoform Composition Influences Rate and Extent of Filament Formation*

Background: Human brain Tau isoforms differ by the presence or absence of inserts derived from alternative splicing of MAPT transcripts. Results: Tau inserts modulate Tau aggregation propensity through differing kinetic mechanisms that synergize or compete depending on sequence context. Conclusion: MAPT splicing patterns associated with tauopathies correlate with aggregation propensity. Significance: Tau aggregation propensity may contribute to disease pathogenesis. The risk of developing tauopathic neurodegenerative disease depends in part on the levels and composition of six naturally occurring Tau isoforms in human brain. These proteins, which form filamentous aggregates in disease, vary only by the presence or absence of three inserts encoded by alternatively spliced exons 2, 3, and 10 of the Tau gene (MAPT). To determine the contribution of alternatively spliced segments to Tau aggregation propensity, the aggregation kinetics of six unmodified, recombinant human Tau isoforms were examined in vitro using electron microscopy assay methods. Aggregation propensity was then compared at the level of elementary rate constants for nucleation and extension phases. We found that all three alternatively spliced segments modulated Tau aggregation but through differing kinetic mechanisms that could synergize or compete depending on sequence context. Overall, segments encoded by exons 2 and 10 promoted aggregation, whereas the segment encoded by exon 3 depressed it with its efficacy dependent on the presence or absence of a fourth microtubule binding repeat. In general, aggregation propensity correlated with genetic risk reported for multiple tauopathies, implicating aggregation as one candidate mechanism rationalizing the correlation between Tau expression patterns and disease.