Tau seeds are subject to aberrant modifications resulting in distinct signatures

The prion-like spread of tau pathology could underlie a spectrum of clinical syndromes including Alzheimer’s disease (AD). Although evidence indicates that tau is transmissible, it is unclear how pathogenic tau seeds are processed in neurons. Here, we analyze fibrillar wild-type and disease-associated P301L tau seeds by using in vitro and neuronal assays. We show that P301L seeds are uniquely modified by post-translational modifications (PTMs) within the microtubule-binding region (MTBR). Although these modifications do not alter tau seed trafficking or localization, acetylated tau variants show accelerated tau aggregation, enhanced tau PTM priming, and prion-like templating. To explain the enhanced tau seed acetylation, we demonstrate that P301L seeds undergo auto-acetylation. Moreover, tau acts generally to inhibit HDAC6 deacetylase activity by preventing HDAC6 phosphorylation, leading to increased substrate acetylation. Our study highlights complex post-translational regulation of transmissible tau seeds and provides insight into the biological properties of tau strains in AD and other tauopathies. [Display omitted] •Tau seeds are internalized and aberrantly modified in neurons•Acetylated tau seeds display pathological properties•HDAC6 is associated with and inhibited by tau seeds•Tau prevents HDAC6 phosphorylation on Ser-22 Tseng et al. show tau seeds are abnormally processed when internalized into neurons. Tau seeds undergo a series of modifications that result as a consequence of auto-acetylation events as well as inhibition of the deacetylase HDAC6. Tau acts as an HDAC6 inhibitor by preventing HDAC6 phosphorylation at Ser-22.