Quantification of Tau Protein Lysine Methylation in Aging and Alzheimer's Disease

J Alzheimers Dis. 2019;71(3):979-991. doi: 10.3233/JAD-190604.


Tau is a microtubule-associated protein that normally interacts in monomeric form with the neuronal cytoskeleton. In Alzheimer's disease, however, it aggregates to form the structural component of neurofibrillary lesions. The transformation is controlled in part by age- and disease-associated post-translational modifications. Recently we reported that tau isolated from cognitively normal human brain was methylated on lysine residues, and that high-stoichiometry methylation depressed tau aggregation propensity in vitro. However, whether methylation stoichiometry reached levels needed to influence aggregation propensity in human brain was unknown. Here we address this problem using liquid chromatography-tandem mass spectrometry approaches and human-derived tau samples. Results revealed that lysine methylation was present in soluble tau isolated from cognitively normal elderly cases at multiple sites that only partially overlapped with the distributions reported for cognitively normal middle aged and AD cohorts, and that the quality of methylation shifted from predominantly dimethyl-lysine to monomethyl-lysine with aging and disease. However, bulk mol methylation/mol tau stoichiometries never exceeded 1 mol methyl group/mol tau protein. We conclude that lysine methylation is a physiological post-translational modification of tau protein that changes qualitatively with aging and disease, and that pharmacological elevation of tau methylation may provide a means for protecting against pathological tau aggregation.

Keywords: Aging; Alzheimer’s disease; mass spectrometry; methylation; phosphorylation; post-translational modification; tau protein.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aged
  • Aged, 80 and over
  • Aging / metabolism*
  • Alzheimer Disease / metabolism*
  • Cells, Cultured
  • Chromatography, High Pressure Liquid
  • Female
  • Humans
  • Lysine / metabolism*
  • Male
  • Metabolomics
  • Methylation
  • Middle Aged
  • Phosphorylation
  • Protein Processing, Post-Translational
  • Proteomics
  • Tandem Mass Spectrometry
  • tau Proteins / chemistry
  • tau Proteins / metabolism*


  • tau Proteins
  • Lysine