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Cited by 101Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

A post-translational modification signature defines changes in soluble tau correlating with oligomerization in early stage Alzheimer's disease brain

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Ercan-Herbst, Ebru, Ehrig, Jens, Schöndorf, David C., Behrendt, Annika, Klaus, Bernd, Gomez Ramos, Borja, Prat Oriol, Nuria, Weber, Christian +1 more·2019·Acta Neuropathologica Communications
DOI 10.1186/s40478-019-0823-2PMC PMC6892178

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Abstract

Tau is a microtubule-binding protein that can receive various post-translational modifications (PTMs) including phosphorylation, methylation, acetylation, glycosylation, nitration, sumoylation and truncation. Hyperphosphorylation of tau is linked to its aggregation and the formation of neurofibrillary tangles (NFTs), which are a hallmark of Alzheimer's disease (AD). While more than 70 phosphorylation sites have been detected previously on NFT tau, studies of oligomeric and detergent-soluble tau in human brains during the early stages of AD are lacking. Here we apply a comprehensive electrochemiluminescence ELISA assay to analyze twenty-five different PTM sites as well as tau oligomerization in control and sporadic AD brain. The samples were classified as Braak stages 0-I, II or III-IV, corresponding to the progression of microscopically detectable tau pathology throughout different brain regions. We found that soluble tau multimers are strongly increased at Braak stages III-IV in all brain regions under investigation, including the temporal cortex, which does not contain NFTs or misfolded oligomers at this stage of pathology. We additionally identified five phosphorylation sites that are specifically and consistently increased across the entorhinal cortex, hippocampus and temporal cortex in the same donors. Three of these sites correlate with tau multimerization in all three brain regions, but do not overlap with the epitopes of phospho-sensitive antibodies commonly used for the immunohistochemical detection of NFTs. Our results thus suggest that soluble multimers are characterized by a small set of specific phosphorylation events that differ from those dominating in mature NFTs. These findings shed light on early PTM changes of tau during AD pathogenesis in human brains.

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  • Previous neuropathological findings highlighted that a key component of pre-tangle pathology was phosphorylation at threonine 231 and that CSF p-tau231 is an important discriminant of Braak 0-I from more advanced Braak stages.

    “Previous neuropathological findings, which motivated the CSF assay development of p-tau231, highlighted that a key component of pre-tangle pathology was phosphorylation at threonine 23155 and that CSF p-tau231 is an important discriminant of Braak 0-I from more advanced Braak stages.56”

    From Cerebrospinal fluid p-tau231 as an early indicator of emerging pathology in Alzheimer's disease (2022) · cites this paper as [56]

    The Discussion links pT231 to pre-tangle structures, and the Results report higher pT231 in brain tissue at Braak III–IV than at Braak 0–I. The paper also says CSF pT231 is increased in AD patients, but it does not show that CSF p-tau231 discriminates between Braak stages; its Braak comparison used brain tissue. In the citing sentence, the citation to this paper is attached to the CSF discrimination claim. (LLM, conf=0.84)

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Authors
Ercan-Herbst, E., Ehrig, J., Schöndorf, D. C., Behrendt, A., Klaus, B., Gomez Ramos, B., Prat Oriol, N., Weber, C., & Ehrnhoefer, D. E.
Affiliations
  • BioMed X (DE)
  • Center for Molecular Bioengineering (DE)
  • European Molecular Biology Laboratory (DE)
Corresponding author
Ehrnhoefer, Dagmar E.
ORCID
Venue
Acta Neuropathologica Communications
Publisher
Springer Science and Business Media LLC
Published
2019-12
Volume
7
Issue
1
Pages
192-192
ISSN
2051-5960 (ISSN-L)
DOI
10.1186/s40478-019-0823-2
PMC
PMC6892178
OpenAlex
W2993562248
Cited by
101
References
12
Citations by year
2026: 3 · 2025: 17 · 2024: 30 · 2023: 14 · 2022: 5 · 2021: 24 · 2020: 7 · 2019: 1
FWCI
6.35
Type
journal article
Language
en
Open access
Licence
Locations
  • Acta Neuropathologica Communications (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
AbbVie Deutschland (n.a.)
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
tau protein, post-translational modification, tau phosphorylation, tau oligomerization, early Alzheimer's disease, Braak stages, neurofibrillary tangles, phospho-specific antibodies, temporal cortex, hippocampus, entorhinal cortex, tau aggregation
MeSH terms
Aged, Aged, 80 and over, Alzheimer Disease, Brain, Female, Humans, Male, Phosphorylation, Protein Processing, Post-Translational, tau Proteins, Induced Pluripotent Stem Cells

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