Tau seeding activity begins in the transentorhinal/entorhinal regions and anticipates phospho-tau pathology in Alzheimer's disease and PART

Acta Neuropathol. 2018 Jul;136(1):57-67. doi: 10.1007/s00401-018-1855-6. Epub 2018 May 11.


Alzheimer's disease (AD) is characterized by accumulation of tau neurofibrillary tangles (NFTs) and, according to the prion model, transcellular propagation of pathological "seeds" may underlie its progression. Staging of NFT pathology with phospho-tau antibody is useful to classify AD and primary age-related tauopathy (PART) cases. The locus coeruleus (LC) shows the earliest phospho-tau signal, whereas other studies suggest that pathology begins in the transentorhinal/entorhinal cortices (TRE/EC). The relationship of tau seeding activity, phospho-tau pathology, and progression of neurodegeneration remains obscure. Consequently, we employed an established cellular biosensor assay to quantify tau seeding activity in fixed human tissue, in parallel with AT8 phospho-tau staining of immediately adjacent sections. We studied four brain regions from each of n = 247 individuals across a range of disease stages. We detected the earliest and most robust seeding activity in the TRE/EC. The LC did not uniformly exhibit seeding activity until later NFT stages. We also detected seeding activity in the superior temporal gyrus (STG) and primary visual cortex (VC) at stages before NFTs and/or AT8-immunopositivity were detectable. AD and putative PART cases exhibited similar patterns of seeding activity that anticipated histopathology across all NFT stages. Our findings are consistent with the prion model and suggest that pathological seeding activity begins in the TRE/EC rather than in the LC. In the analysis of tauopathy, quantification of seeding activity may offer an important addition to classical histopathology.

Keywords: Alzheimer’s disease; FRET biosensor; Neurofibrillary tangles; Prion propagation; Tau seeding activity, Tau staging.

Publication types

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

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / pathology*
  • Animals
  • Disease Progression
  • Entorhinal Cortex / metabolism*
  • Female
  • Gene Expression Regulation / genetics
  • HEK293 Cells
  • Humans
  • Locus Coeruleus / metabolism
  • Locus Coeruleus / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microfilament Proteins / metabolism
  • Middle Aged
  • Neurofibrillary Tangles / metabolism
  • Neurofibrillary Tangles / pathology
  • Phosphorylation
  • Tauopathies / pathology*
  • Temporal Lobe / metabolism*
  • Visual Cortex / metabolism*
  • Young Adult
  • tau Proteins / genetics
  • tau Proteins / metabolism*


  • Microfilament Proteins
  • tau Proteins