Biomarker-related phospho-tau217 appears in synapses around Aβ plaques prior to tau tangle in cerebral cortex of preclinical Alzheimer’s disease
Phospho-tau protein p-tau181 is a cerebrospinal fluid biomarker for Alzheimer's disease (AD), while p-tau217 is the most sensitive plasma biomarker for cerebral amyloid β (Aβ) load prior to tau pathology in preclinical AD. Diagnostic and prognostic use of these p-tau biomarkers requires neuropathological interpretation. Here, we analyzed the cellular localization of biomarker p-tau species in postmortem human brains harboring different extents of Aβ plaque and tau pathology. Signals for p-tau217 were absent in normal brains but present in pre- and post-synapses surrounding Aβ plaques in preclinical AD brains. p-Tau217 colocalized with tau pathology markers p-tau202/205, p-tau231, and p-tau262, while p-tau181 was normally present in glutamatergic and GABAergic axons, which were distorted around Aβ plaques, where p-tau217 and p-tau181 colocalized. p-tau217-containing pre-synapses were enriched with active tau kinases and were not preferentially engulfed by glial cells. Emergence of p-tau217 represents a neuronal/synaptic reaction to Aβ plaques in preclinical AD brains.
Authors
- Shigeo Murayama (ORCID: https://orcid.org/0000-0001-9709-5242)
- Michiko Sekiya (ORCID: https://orcid.org/0000-0001-8275-8293)
- Maho Morishima
- Yu Hirota (ORCID: https://orcid.org/0000-0002-7107-2197)
- Yasufumi Sakakibara (ORCID: https://orcid.org/0000-0002-7459-1611)
- Akira Arakawa (ORCID: https://orcid.org/0000-0002-9336-1168)
- Terunori Sano (ORCID: https://orcid.org/0000-0001-8967-5984)
- Takao Masaki (ORCID: https://orcid.org/0000-0003-4271-9964)
- Koichi Iijima (ORCID: https://orcid.org/0000-0003-4794-1863)
- Yuko Saito (ORCID: https://orcid.org/0000-0002-9974-8638)
- Manato Hara
Institutions
- National Center of Neurology and Psychiatry (JP)
- Tokyo Metropolitan Institute of Gerontology (JP)
- Tokyo Metropolitan Geriatric Hospital (JP)
- National Center for Geriatrics and Gerontology (JP)
Publication Details
- Journal
- Cell Reports
- Published
- 2025-09-01
- DOI
- https://doi.org/10.1016/j.celrep.2025.116203
- Citations
- 5
- Primary Topic
- Alzheimer's disease research and treatments
- Type
- article
- Field-Weighted Citation Impact
- 5.82
Funders
- Japan Agency for Medical Research and Development
- Ministry of Health, Labour and Welfare
- Hori Sciences and Arts Foundation
- National Center for Geriatrics and Gerontology
- National Center of Neurology and Psychiatry
- Japan Society for the Promotion of Science
- Exploratory Research Center on Life and Living Systems, National Institutes of Natural Sciences