A unique tau conformation generated by an acetylation-mimic substitution modulates P301S-dependent tau pathology and hyperphosphorylation

J Biol Chem. 2019 Nov 8;294(45):16698-16711. doi: 10.1074/jbc.RA119.009674. Epub 2019 Sep 22.


Abnormal intracellular accumulation of aggregated tau is a hallmark feature of Alzheimer's disease and other tauopathies. Pathological tau can undergo a range of post-translational modifications (PTMs) that are implicated as triggers of disease pathology. Recent studies now indicate that tau acetylation, in particular, controls both microtubule binding and tau aggregation, thereby acting as a central regulator of tau's biochemical properties and providing avenues to exploit for potential therapies. Here, using cell-based assays and tau transgenic mice harboring an acetylation-mimic mutation at residue Lys-280 (K280Q), we evaluated whether this substitution modifies the neurodegenerative disease pathology associated with the aggregate-prone tau P301S variant. Strikingly, the addition of a K280Q-substituted variant altered P301S-mediated tau conformation and reduced tau hyperphosphorylation. We further evaluated neurodegeneration markers in K280Q acetylation-mimic mice and observed reduced neuroinflammation as well as restored levels of N-methyl-d-aspartate receptors and post-synaptic markers compared with the parental mice. Thus, substituting a single lysine residue in the context of a P301S disease-linked mutation produces a unique tau species that abrogates some of the cardinal features of tauopathy. The findings of our study indicate that a complex tau PTM code likely regulates tau pathogenesis, highlighting the potential utility of manipulating and detoxifying tau strains through site-specific tau-targeting approaches.

Keywords: Alzheimer disease; acetylation; excitotoxicity; neuroinflammation; post-translational modification (PTM); tau protein (tau).

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Animals
  • Cerebral Cortex / metabolism
  • Cerebral Cortex / pathology
  • Hippocampus / metabolism
  • Hippocampus / pathology
  • Kaplan-Meier Estimate
  • Lysine / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mutagenesis, Site-Directed
  • Phosphorylation
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Tauopathies / metabolism
  • Tauopathies / mortality
  • Tauopathies / pathology*
  • tau Proteins / genetics
  • tau Proteins / metabolism*


  • Receptors, N-Methyl-D-Aspartate
  • tau Proteins
  • Lysine