Tau protein liquid-liquid phase separation can initiate tau aggregation

EMBO J. 2018 Apr 3;37(7):e98049. doi: 10.15252/embj.201798049. Epub 2018 Feb 22.


The transition between soluble intrinsically disordered tau protein and aggregated tau in neurofibrillary tangles in Alzheimer's disease is unknown. Here, we propose that soluble tau species can undergo liquid-liquid phase separation (LLPS) under cellular conditions and that phase-separated tau droplets can serve as an intermediate toward tau aggregate formation. We demonstrate that phosphorylated or mutant aggregation prone recombinant tau undergoes LLPS, as does high molecular weight soluble phospho-tau isolated from human Alzheimer brain. Droplet-like tau can also be observed in neurons and other cells. We found that tau droplets become gel-like in minutes, and over days start to spontaneously form thioflavin-S-positive tau aggregates that are competent of seeding cellular tau aggregation. Since analogous LLPS observations have been made for FUS, hnRNPA1, and TDP43, which aggregate in the context of amyotrophic lateral sclerosis, we suggest that LLPS represents a biophysical process with a role in multiple different neurodegenerative diseases.

Keywords: Alzheimer's disease; aggregation; liquid–liquid phase separation; phosphorylation; tau.

Publication types

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

MeSH terms

  • Aged, 80 and over
  • Alzheimer Disease / metabolism*
  • Amino Acid Sequence
  • Amyotrophic Lateral Sclerosis / metabolism*
  • Animals
  • Benzothiazoles / metabolism
  • Biophysical Phenomena
  • Brain / metabolism*
  • Cloning, Molecular
  • DNA-Binding Proteins / metabolism
  • Escherichia coli / genetics
  • Female
  • HEK293 Cells
  • Heterogeneous Nuclear Ribonucleoprotein A1 / metabolism
  • Humans
  • Liquid-Liquid Extraction
  • Mice
  • Mice, Transgenic
  • Molecular Weight
  • Neuroblastoma / metabolism
  • Neurodegenerative Diseases / metabolism
  • Neurofibrillary Tangles / metabolism
  • Neurons / metabolism*
  • Phosphorylation
  • Protein Aggregation, Pathological / metabolism*
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Sequence Analysis, Protein
  • Sf9 Cells
  • tau Proteins / chemistry*
  • tau Proteins / isolation & purification*
  • tau Proteins / metabolism*


  • Benzothiazoles
  • DNA-Binding Proteins
  • Heterogeneous Nuclear Ribonucleoprotein A1
  • Recombinant Proteins
  • TARDBP protein, human
  • hnRNPA1 protein, human
  • tau Proteins
  • thioflavin T