Tau seeding activity begins in the transentorhinal/entorhinal regions and anticipates phospho-tau pathology in Alzheimer’s disease and PART
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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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Seeding precedes tau pathogenesis and can even occur in brain regions where tau pathology does not usually present.
“Several studies have shown that seeding precedes tau pathogenesis and can even occur in brain regions where tau pathology does not usually present (DeVos et al., 2018; Kaufman et al., 2018; Stopschinski et al., 2021).”
From Network analysis identifies strain-dependent response to tau and tau seeding-associated genes (2023) · cites this paper as Kaufman et al., 2018
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- 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.
- Venue
- Acta Neuropathologica
- Published
- 2018-05-11
- Volume
- 136
- Issue
- 1
- Pages
- 57-67
- ISSN
- 0001-6322 (ISSN-L)
- 1432-0533
- 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
- hybrid
- doi.org
- 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
- Health Sciences › Medicine › Physiology › 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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