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Cited by 259Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

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

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Kaufman, Sarah K., Del Tredici, Kelly, Thomas, Talitha L., Braak, Heiko, Diamond, Marc I.·2018·Acta Neuropathologica
DOI 10.1007/s00401-018-1855-6PMC PMC6015098

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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.

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Fig. 1 Tau seeding assay reliably detects tau aggregate pathology in formaldehyde-fixed tissue from neuropathologically staged cases. Seeding activity from adjacent punch biopsies correlated significantly with one another (n = 247, p < 0.0001). Two adjacent punch biopsies were taken from the TRE/EC region and tested for phospho-tau seeding activity. Seeding activity correlated well between punches. Spearman r and p values are displayed on the graph
Fig. 1 Tau seeding assay reliably detects tau aggregate pathology in formaldehyde-fixed tissue from neuropathologically staged cases. Seeding activity from adjacent punch biopsies correlated significantly with one another (n = 247, p < 0.0001). Two adjacent punch biopsies were taken from the TRE/EC region and tested for phospho-tau seeding activity. Seeding activity correlated well between punches. Spearman r and p values are displayed on the graphCC BY · PubMed Central
Fig. 2 Tau seeding activity across brain regions. Tau seeding activity and tau staging was performed blinded for each of four brain regions in n = 247 subjects: TRE/EC, LC, STG (Brodmann Area 22), and primary VC (Brodmann Area 17, striate area). For cortical pretangle stage 1b, samples were taken only from the LC and TRE/EC. a Seeding activity was first observed in the TRE/EC at stage 1b, and increased several-fold at later NFT stages. Every individual examined showed positivity in this region by NFT stage IV. b Seeding in the LC was first detectable at NFT stage I in a small number of cases. Most samples exhibited tau seeding by NFT stage III. c Seeding activity in the STG was observed in a limited number of cases by NFT stage II and increased at later stages. d The primary VC displayed positive seeding activity as early as NFT stage III, but approximately 15% of the individuals sampled did not show positivity even at NFT stage VI. KO = tau knockout mouse brain. Threshold values were set at 4SD above tau KO negative control samples. Kruskal-Wallis one-way ANOVA comparing TRE/EC tau stage 1b vs tau KO controls and LC stage 1b vs tau KO controls demonstrated significant seeding activity only in the TRE/EC (++++ = p < 0.0001). Additional Kruskal-Wallis ANOVA analysis was performed by comparing tau stages within each brain region to tau KO controls. Error bars = S.E.M, *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001
Fig. 2 Tau seeding activity across brain regions. Tau seeding activity and tau staging was performed blinded for each of four brain regions in n = 247 subjects: TRE/EC, LC, STG (Brodmann Area 22), and primary VC (Brodmann Area 17, striate area). For cortical pretangle stage 1b, samples were taken only from the LC and TRE/EC. a Seeding activity was first observed in the TRE/EC at stage 1b, and increased several-fold at later NFT stages. Every individual examined showed positivity in this region by NFT stage IV. b Seeding in the LC was first detectable at NFT stage I in a small number of cases. Most samples exhibited tau seeding by NFT stage III. c Seeding activity in the STG was observed in a limited number of cases by NFT stage II and increased at later stages. d The primary VC displayed positive seeding activity as early as NFT stage III, but approximately 15% of the individuals sampled did not show positivity even at NFT stage VI. KO = tau knockout mouse brain. Threshold values were set at 4SD above tau KO negative control samples. Kruskal-Wallis one-way ANOVA comparing TRE/EC tau stage 1b vs tau KO controls and LC stage 1b vs tau KO controls demonstrated significant seeding activity only in the TRE/EC (++++ = p < 0.0001). Additional Kruskal-Wallis ANOVA analysis was performed by comparing tau stages within each brain region to tau KO controls. Error bars = S.E.M, *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001CC BY · PubMed Central
Fig. 3 Tau seeding activity versus semiquantitative AT8 histopathology. Seeding activity and AT8 histopathology were each performed blinded, and the results compared. a Subjects with a range of AT8 tau pathology (0, (+), +, ++, +++) displayed robust seeding activity in the TRE/EC. Subjects with a higher degree of AT8 signal displayed higher levels of seeding activity. b Tau seeding activity in the LC was compared to AT8 signal. Subjects with mild to moderate tau AT8 pathology (levels (+) to ++) had a range of seeding activities, and a substantive number exhibited no seeding activity despite AT8 signal. c Seeding in the STG was detectable prior to AT8 pathology in several AD and PART brain samples. d Seeding in the primary VC could be detected prior to an AT8 signal in multiple AD and PART brain samples. Note: PART subjects only spanned NFT stages 1b-IV
Fig. 3 Tau seeding activity versus semiquantitative AT8 histopathology. Seeding activity and AT8 histopathology were each performed blinded, and the results compared. a Subjects with a range of AT8 tau pathology (0, (+), +, ++, +++) displayed robust seeding activity in the TRE/EC. Subjects with a higher degree of AT8 signal displayed higher levels of seeding activity. b Tau seeding activity in the LC was compared to AT8 signal. Subjects with mild to moderate tau AT8 pathology (levels (+) to ++) had a range of seeding activities, and a substantive number exhibited no seeding activity despite AT8 signal. c Seeding in the STG was detectable prior to AT8 pathology in several AD and PART brain samples. d Seeding in the primary VC could be detected prior to an AT8 signal in multiple AD and PART brain samples. Note: PART subjects only spanned NFT stages 1b-IVCC BY · PubMed Central
Fig. 4 Correlations of tau seeding activity across brain regions. a Tau seeding activity was typically observed in the TRE/EC before seeding in the LC and was higher in this brain region for the majority of subjects. Spearman r and p values are displayed on the graph. b Seeding typically appeared first in the TRE/EC and at higher levels than in the STG or c the primary VC. Spearman r and p values are displayed on the graph
Fig. 4 Correlations of tau seeding activity across brain regions. a Tau seeding activity was typically observed in the TRE/EC before seeding in the LC and was higher in this brain region for the majority of subjects. Spearman r and p values are displayed on the graph. b Seeding typically appeared first in the TRE/EC and at higher levels than in the STG or c the primary VC. Spearman r and p values are displayed on the graphCC BY · PubMed Central
Fig. 5 Tau seeding activity across multiple brain regions for individual AD and PART cases. Cases were categorized as AD vs. PART based on neuropathological criteria. Samples from each individual were directly compared across multiple brain regions. A continuous heat map of tau seeding activity (logarithmic scale) was plotted for each case and organized by staging and disease entity (AD, PART). AD subjects were arranged within each stage from low to high Aβ. Gray boxes represent unavailable samples. Tau seeding in the TRE/EC increased first and remained high for each disease stage. Subjects typically displayed less seeding in the LC, STG and primary VC vs. the TRE/EC. The level of tau seeding in these secondary brain regions was higher at later tau stages. Cases categorized as “definite PART” (Aβ phase 0) displayed a similar trend for the spatiotemporal progression of seeding activity when compared to AD. Grey boxes indicate absent samples
Fig. 5 Tau seeding activity across multiple brain regions for individual AD and PART cases. Cases were categorized as AD vs. PART based on neuropathological criteria. Samples from each individual were directly compared across multiple brain regions. A continuous heat map of tau seeding activity (logarithmic scale) was plotted for each case and organized by staging and disease entity (AD, PART). AD subjects were arranged within each stage from low to high Aβ. Gray boxes represent unavailable samples. Tau seeding in the TRE/EC increased first and remained high for each disease stage. Subjects typically displayed less seeding in the LC, STG and primary VC vs. the TRE/EC. The level of tau seeding in these secondary brain regions was higher at later tau stages. Cases categorized as “definite PART” (Aβ phase 0) displayed a similar trend for the spatiotemporal progression of seeding activity when compared to AD. Grey boxes indicate absent samplesCC BY · PubMed Central

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Metadata

Authors
Kaufman, S. K., Del Tredici, K., Thomas, T. L., Braak, H., & Diamond, M. I.
Affiliations
  • Washington University in St. Louis (US)
  • The University of Texas Southwestern Medical Center (US)
  • Universität Ulm (DE)
Corresponding author
Diamond, Marc I.
ORCID
Venue
Acta Neuropathologica
Publisher
Springer Science and Business Media LLC
Published
2018-05-11
Volume
136
Issue
1
Pages
57-67
ISSN
  • 0001-6322 (ISSN-L)
  • 1432-0533
DOI
10.1007/s00401-018-1855-6
PMC
PMC6015098
OpenAlex
W2799729840
Cited by
259
References
46
Citations by year
2026: 15 · 2025: 40 · 2024: 30 · 2023: 41 · 2022: 19 · 2021: 43 · 2020: 28 · 2019: 32 · 2018: 10
FWCI
19.42
Type
journal article
Language
en
Open access
Licence
Locations
  • Acta Neuropathologica (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • Rainwater Charitable Foundation (n/a)
  • National Institute on Aging (R01AG048678)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
Alzheimer's disease, primary age-related tauopathy, locus coeruleus, neurofibrillary tangles, AT8 antibody, superior temporal gyrus, primary visual cortex, disease staging
MeSH terms
Adolescent, Adult, Aged, Aged, 80 and over, Alzheimer Disease, Animals, Female, Gene Expression Regulation, Humans, Locus Coeruleus, Male, Mice, Inbred C57BL, Microfilament Proteins, Middle Aged, Phosphorylation, Temporal Lobe, Visual Cortex, Neurofibrillary Tangles, tau Proteins, Mice, Knockout, Disease Progression, Entorhinal Cortex, Tauopathies, Mice, Young Adult, HEK293 Cells

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