The human brain acetylome reveals that decreased acetylation of mitochondrial proteins associates with Alzheimer's disease

J Neurochem. 2021 Jul;158(2):282-296. doi: 10.1111/jnc.15377. Epub 2021 May 12.


Metabolic changes that correlate to cognitive changes are well-known in Alzheimer's disease (AD). Metabolism is often linked to functional changes in proteins by post-translational modifications. The importance of the regulation of transcription by acetylation is well documented. Advanced mass spectrometry reveals hundreds of acetylated proteins in multiple tissues, but the acetylome of human brain, its functional significance, and the changes with disease are unknown. Filling this gap is critical for understanding the pathophysiology and development of therapies. To fill this gap, we assessed the human brain acetylome in human brain and its changes with AD. More than 5% of the 4,442 proteins from the human brain global proteome were acetylated. Acetylated proteins were primarily found in the cytosol (148), mitochondria (100), nucleus (91), and plasma membrane (58). The comparison of the brain acetylome in controls to that of patients with AD revealed striking and selective differences in terms of its abundances of acetylated peptides/sites. Acetylation of 18 mitochondrial proteins decreased, while acetylation of two cytosolic proteins, tau and GFAP, increased. Our experiments demonstrate that acetylation at some specific lysine sites alters enzyme function. The results indicate that general activation of de-acetylases (i.e., sirtuins) is not an appropriate therapeutic approach for AD.

Keywords: Alzheimer; acetylation; human brain; ketoglutarate dehydrogenase complex; pyruvate dehydrogenase complex; s disease.

Publication types

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

MeSH terms

  • Acetylation*
  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / genetics*
  • Alzheimer Disease / metabolism*
  • Brain Chemistry
  • Computational Biology
  • Female
  • Glial Fibrillary Acidic Protein / metabolism
  • Humans
  • Ketoglutarate Dehydrogenase Complex / metabolism
  • Lysine / metabolism
  • Male
  • Metabolome / genetics*
  • Mitochondrial Proteins / metabolism*
  • Protein Processing, Post-Translational
  • Pyruvate Dehydrogenase Complex / metabolism
  • Subcellular Fractions / metabolism
  • tau Proteins / metabolism


  • GFAP protein, human
  • Glial Fibrillary Acidic Protein
  • MAPT protein, human
  • Mitochondrial Proteins
  • Pyruvate Dehydrogenase Complex
  • tau Proteins
  • Ketoglutarate Dehydrogenase Complex
  • Lysine