Phospho-tau serine-262 and serine-356 as biomarkers of pre-tangle soluble tau assemblies in Alzheimer’s disease

Patients with Alzheimer's disease (AD) with little or no quantifiable insoluble brain tau neurofibrillary tangle (NFT) pathology demonstrate stronger clinical benefits of therapies than those with advanced NFTs. The formation of NFTs can be prevented by targeting the intermediate soluble tau assemblies (STAs). However, biochemical understanding and biomarkers of STAs are lacking. We show that Tris-buffered saline-soluble tau aggregates from autopsy-verified AD brain tissues include the core sequence ~tau<sub>258-368</sub>. In neuropathological assessments, antibodies against the phosphorylation sites serine-262 and serine-356 within the STA core almost exclusively stained granular (that is, prefibrillar) tau aggregates in pre-NFTs while antibodies against phosphorylation at serine-202 and threonine-205 and threonine-231, outside the STA core, stained the entire spectrum of tau aggregates in pre-NFTs and mature NFTs, dystrophic neurites and neuropil threads in the hippocampus. Functionally, a recombinantly produced STA core peptide robustly altered neuronal excitability and synaptic transmission in mouse hippocampal brain slices. Furthermore, we developed a cerebrospinal fluid assay that differentiated STAs in AD from non-AD tauopathies, correlated with the severity of NFT burden and cognitive decline independently of amyloid beta deposition, and with tau positron emission tomography uptake across Braak NFT stages. Together, our findings inform about the status of early-stage tau aggregation, reveal aggregation-relevant phosphorylation epitopes in tau and offer a diagnostic biomarker and targeted therapeutic opportunities for AD.

Authors

Institutions

Publication Details

Journal
Nature Medicine
Published
2025-02-01
DOI
https://doi.org/10.1038/s41591-024-03400-0
Citations
46
Primary Topic
Alzheimer's disease research and treatments
Type
article
Field-Weighted Citation Impact
53.56

Funders

Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

Phospho-tau serine-262 and serine-356 as biomarkers of pre-tangle soluble tau assemblies in Alzheimer’s disease

Tharick Ali Pascoal, Anna Richardson, Joseph Therriault, Xuemei Zeng et al.
46 citations
Nature Medicine
Alzheimer's disease research and treatments
53.56
article

Phospho-tau serine-262 and serine-356 as biomarkers of pre-tangle soluble tau assemblies in Alzheimer’s disease

Tharick Ali Pascoal, Anna Richardson, Joseph Therriault, Xuemei Zeng, Emily Hill, Miloš D. Ikonomović, Kaj Blennow, Hlin Kvartsberg, Fernando González‐Ortiz, Mark J. Wall, Przemysław Radosław Kac, Nesrine Rahmouni, Tammaryn Lashley, Anuradha Sehrawat, Maria Olsson, Thomas K. Karikari, Stijn Servaes, Eric E. Abrahamson, Violaine Mitchell, Cécile Tissot, Douglas R Galasko, Emma Sjons, Denis S. Smirnov, Henrik Zetterberg, Ivana Del Popolo, Pedro Rosa‐Neto, Yijun Chen, Tohidul Islam
article en
46 citations

Abstract

Patients with Alzheimer's disease (AD) with little or no quantifiable insoluble brain tau neurofibrillary tangle (NFT) pathology demonstrate stronger clinical benefits of therapies than those with advanced NFTs. The formation of NFTs can be prevented by targeting the intermediate soluble tau assemblies (STAs). However, biochemical understanding and biomarkers of STAs are lacking. We show that Tris-buffered saline-soluble tau aggregates from autopsy-verified AD brain tissues include the core sequence ~tau<sub>258-368</sub>. In neuropathological assessments, antibodies against the phosphorylation sites serine-262 and serine-356 within the STA core almost exclusively stained granular (that is, prefibrillar) tau aggregates in pre-NFTs while antibodies against phosphorylation at serine-202 and threonine-205 and threonine-231, outside the STA core, stained the entire spectrum of tau aggregates in pre-NFTs and mature NFTs, dystrophic neurites and neuropil threads in the hippocampus. Functionally, a recombinantly produced STA core peptide robustly altered neuronal excitability and synaptic transmission in mouse hippocampal brain slices. Furthermore, we developed a cerebrospinal fluid assay that differentiated STAs in AD from non-AD tauopathies, correlated with the severity of NFT burden and cognitive decline independently of amyloid beta deposition, and with tau positron emission tomography uptake across Braak NFT stages. Together, our findings inform about the status of early-stage tau aggregation, reveal aggregation-relevant phosphorylation epitopes in tau and offer a diagnostic biomarker and targeted therapeutic opportunities for AD.

Nature MedicineVol. 31(2)
Brigham and Women's Hospital (US), Montreal Neurological Institute and Hospital (CA), University of Wisconsin–Madison (US), University of Pittsburgh (US), Sahlgrenska University Hospital (SE), University of California San Diego (US), University of Warwick (GB), UPMC Health System (US), Geriatric Research Education and Clinical Center (US), UK Dementia Research Institute (GB), MRC Prion Unit (GB), National Hospital for Neurology and Neurosurgery (GB), University College London (GB), McGill University (CA), University of Gothenburg (SE)
Alzheimer's Association, Brigham and Women's Hospital, Massachusetts General Hospital, University of Wisconsin-Madison, Familjen Erling-Perssons Stiftelse, University of Pittsburgh, McGill University, Fondation Brain Canada, Weston Brain Institute, EU Joint Programme – Neurodegenerative Disease Research, Consortium canadien en neurodégénérescence associée au vieillissement, National Institute for Health and Care Research, University of Warwick, University College London, European Commission, Hjärnfonden, Vetenskapsrådet, Sahlgrenska Universitetssjukhuset, Göteborgs Universitet, UK Dementia Research Institute, Fondation pour la Recherche sur Alzheimer, National Institutes of Health, University of California, San Diego, School of Medicine and Public Health, University of Wisconsin-Madison, Geriatric Research Education and Clinical Center, HORIZON EUROPE Framework Programme, Canadian Institutes of Health Research, Fonds de Recherche du Québec - Santé, Sahlgrenska Akademin, National Institute on Aging, NIH Clinical Center
Good health and well-being
Openalex Percentile: Top 0%
Alzheimer's disease research and treatments
53.56
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.