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

Sarah K. Kaufman, Kelly Del Tredici, Talitha L. Thomas, Heiko Braak, Marc I. Diamond

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1-11
Number of pages11
JournalActa Neuropathologica
DOIs
StateAccepted/In press - May 11 2018

Fingerprint

Tauopathies
Neurofibrillary Tangles
Alzheimer Disease
Entorhinal Cortex
Locus Coeruleus
Pathology
Prions
Biosensing Techniques
Visual Cortex
Temporal Lobe
Seeds
Staining and Labeling
Antibodies
Brain

Keywords

  • Alzheimer’s disease
  • FRET biosensor
  • Neurofibrillary tangles
  • Prion propagation
  • Tau seeding activity, Tau staging

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

Cite this

Tau seeding activity begins in the transentorhinal/entorhinal regions and anticipates phospho-tau pathology in Alzheimer’s disease and PART. / Kaufman, Sarah K.; Del Tredici, Kelly; Thomas, Talitha L.; Braak, Heiko; Diamond, Marc I.

In: Acta Neuropathologica, 11.05.2018, p. 1-11.

Research output: Contribution to journalArticle

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