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Biomarker-related phospho-tau217 appears in synapses around Aβ plaques prior to tau tangle in cerebral cortex of preclinical Alzheimer's disease.

Y. Hirota,Yasufumi Sakakibara,M. Morishima,Terunori Sano,Manato Hara,Akira Arakawa,Masaki Takao,Shigeo Murayama,Yuko Saito,M. Sekiya,K. Iijima

Published 2025 in Cell Reports

ABSTRACT

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.

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