Major differences between the self-assembly and seeding behavior of heparin-induced- and in-vitro-phosphorylated tau and their modulation by potential inhibitors

Self-assembly of the microtubule-associated protein tau into neurotoxic oligomers, fibrils, and paired helical filaments, and cell-to-cell spreading of these pathological tau species are critical processes underlying the pathogenesis of Alzheimer’s disease (AD) and other tauopathies. Modulating the self-assembly process and inhibiting formation and spreading of such toxic species are promising strategies for therapy development. A challenge in investigating tau self-assembly in vitro is that unlike most amyloidogenic proteins, tau does not aggregate in the absence of posttranslational modifications (PTM), aggregation inducers, or pre-formed seeds. The most common induction method is addition of polyanions, such as heparin, yet this artificial system may not represent adequately tau self-assembly in vivo, which is driven by aberrant phosphorylation and other PTMs, potentially leading to in-vitro data that do not reflect the behavior of tau and its interaction with modulators in vivo. To tackle these challe...