A Distinct Tau Code Controlled by HDAC6 is Linked to Tau Pathogenesis and the Neuronal Stress Response

The prion-like spread of tau pathology could underlie a spectrum of distinct clinical syndromes including Alzheimer’s disease (AD). Although evidence indicates that tau is transmissible, it is unclear how pathogenic tau species evolve in neurons. Here, we analyzed fibrillar tau seeds comprising wild-type or disease-associated P301L tau using in vitro and neuronal-based assays. Unexpectedly, we show that P301L seeds are distinctly modified via post-translational modifications (PTMs) within the microtubule-binding region (MTBR). While these modifications do not alter tau seed trafficking or localization, acetylated tau showed accelerated tau aggregation kinetics, enhanced priming of nearby tau PTMs, and prion-like templating. To explain their susceptibility to acetylation, we show that P301L seeds undergo auto-acetylation and also preferentially inhibit the deacetylase HDAC6. We further identify a coordinated tau-HDAC6 signaling axis, as tau depletion activates HDAC6 and globally alters the stress-responsive acetylome. Our study highlights the complex post-translational regulation of transmissible tau seeds and provides new insight into the biological properties of tau strains in AD and other tauopathies.