A Dual Pathogenic Mechanism Links Tau Acetylation to Sporadic Tauopathy

Hanna Trzeciakiewicz,Connor M Wander,Chao-Xing Yuan,Victoria Madden,Ashutosh Tripathy,Jui-Heng Tseng,Todd J Cohen

doi:10.1038/srep44102

Hanna Trzeciakiewicz, Connor M Wander + Show 5 more

Open Access

https://doi.org/10.1038/srep44102

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Abstract

Tau acetylation has recently emerged as a dominant post-translational modification (PTM) in Alzheimer’s disease (AD) and related tauopathies. Mass spectrometry studies indicate that tau acetylation sites cluster within the microtubule (MT)-binding region (MTBR), suggesting acetylation could regulate both normal and pathological tau functions. Here, we combined biochemical and cell-based approaches to uncover a dual pathogenic mechanism mediated by tau acetylation. We show that acetylation specifically at residues K280/K281 impairs tau-mediated MT stabilization, and enhances the formation of fibrillar tau aggregates, highlighting both loss and gain of tau function. Full-length acetylation-mimic tau showed increased propensity to undergo seed-dependent aggregation, revealing a potential role for tau acetylation in the propagation of tau pathology. We also demonstrate that methylene blue, a reported tau aggregation inhibitor, modulates tau acetylation, a novel mechanism of action for this class of compounds. Our study identifies a potential “two-hit” mechanism in which tau acetylation disengages tau from MTs and also promotes tau aggregation. Thus, therapeutic approaches to limit tau K280/K281 acetylation could simultaneously restore MT stability and ameliorate tau pathology in AD and related tauopathies.

Highlights

We and others demonstrated that tau is subject to acetylation within the lysine-rich MTBR4–9
We observed that CREB-binding protein (CBP)-acetylated tau led to specific loss of the slower migrating ~75 kD tau species, initially detected using total tau antibodies, which potentially reflected reduced phosphorylation mediated by tau acetylation, an effect that was not observed with CBP-LD that is unable to facilitate tau acetylation (Fig. 1a, Supplementary Fig. S1)
Given that acetylated tau is detected within NFTs in Alzheimer’s disease (AD) brain[4,11,12], we investigated whether acetylation might promote tau aggregation, as our previous study using CBP-acetylated tau suggested that fully acetylated tau induced tau aggregation in vitro[4], the critical residues mediating this effect remained unclear

Summary

Introduction

We and others demonstrated that tau is subject to acetylation within the lysine-rich MTBR4–9. While the full complement of enzymes controlling tau acetylation is not well-characterized, in vitro and cell-based experiments showed that CREB-binding protein (CBP) or the highly homologous p300 acetylates tau with high affinity in the MTBR4,8,10. Tau acetylation-mimicking mutations at other prominent sites including K174, K274, K281 induced a series of AD-like deficits including synaptic dysfunction, neuronal loss, and cognitive impairments in viral-transduced and transgenic mouse models, supporting an acetylation-mediated pathological cascade[15,16]. Biochemical studies showed that the positively charged tau residues K280 and K281 physically engage MTs, highlighting the double lysine containing PHF6* motif (275VQIINK/K281) in exon 10 as a hotspot for tau-MT binding in addition to promoting tau aggregation[17]. Either lysine deletion or acetylation is predicted to neutralize the overall positive lysine charge within this region, potentially abrogating tau-MT binding. In contrast to the relatively rare genetic ΔK280 mutation, positive K280-acetylated lesions are observed in most sporadic 4R-tauopathies analyzed to date[11,12] and may represent a common feature of AD and other tauopathies

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