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


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Article Info

DATE

2018-05-11

AUTHORS

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

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. More... »

PAGES

57-67

References to SciGraph publications

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  • 2016-03-18. A critical appraisal of the pathogenic protein spread hypothesis of neurodegeneration in NATURE REVIEWS NEUROSCIENCE
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  • 2009-06-07. Transmission and spreading of tauopathy in transgenic mouse brain in NATURE CELL BIOLOGY
  • 2015-01-28. PART is part of Alzheimer disease in ACTA NEUROPATHOLOGICA
  • 2015-10-07. Propagation of alpha-synuclein pathology: hypotheses, discoveries, and yet unresolved questions from experimental and human brain studies in ACTA NEUROPATHOLOGICA
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  • 2009-04-21. Classification and basic pathology of Alzheimer disease in ACTA NEUROPATHOLOGICA
  • 2016-11-22. Widespread tau seeding activity at early Braak stages in ACTA NEUROPATHOLOGICA
  • 2017-06-07. Characterization of tau prion seeding activity and strains from formaldehyde-fixed tissue in ACTA NEUROPATHOLOGICA COMMUNICATIONS
  • 2001-01. Neurotrophins are required for nerve growth during development in NATURE NEUROSCIENCE
  • 2014-10-28. Primary age-related tauopathy (PART): a common pathology associated with human aging in ACTA NEUROPATHOLOGICA
  • 2011-12-11. Hyperphosphorylated tau in young and middle-aged subjects in ACTA NEUROPATHOLOGICA
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  • 2011-04-24. Alzheimer’s pathogenesis: is there neuron-to-neuron propagation? in ACTA NEUROPATHOLOGICA
  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1007/s00401-018-1855-6

    DOI

    http://dx.doi.org/10.1007/s00401-018-1855-6

    DIMENSIONS

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    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/29752551


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    49 schema:description 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.
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