Journal Article

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

Gonzalez-Ortiz, Fernando, Del Popolo, Ivana, Hill, Emily, Olsson, Maria, Chen, Yijun, Tissot, Cécile, Kvartsberg, Hlin, Richardson, Abbie, Sjons, Emma, Servaes, Stijn, Pascoal, Tharick A., Lashley, Tammaryn, Sehrawat, Anuradha, Smirnov, Denis S., Islam, Tohidul, Therriault, Joseph, Galasko, Douglas, Mitchell, Victoria, Kac, Przemysław R., Zetterberg, Henrik, Zeng, Xuemei, Rosa-Neto, Pedro, Wall, Mark J., Abrahamson, Eric E., Rahmouni, Nesrine, Blennow, Kaj, Karikari, Thomas K., Ikonomovic, Milos D.

2025

Overview

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 258–368 . 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. Two new phosphorylation sites, p-tau 262 and p-tau 356 , detect the formation of prefibrillar tau aggregates and may serve as early-stage biofluid-based biomarkers of tau neurofibrillary tangle pathology in Alzheimer’s disease.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/45/882 / 692/617/375/365/1283 / Aged / Aged, 80 and over / Aggregates / Alzheimer Disease - cerebrospinal fluid / Alzheimer Disease - metabolism / Alzheimer Disease - pathology / Alzheimer's disease / Animals / Annan medicin och hälsovetenskap / Antibodies / Assemblies / Autopsies / Autopsy / Axons / Biomarkers / Biomarkers - cerebrospinal fluid / Biomarkers - metabolism / Biomedical and Life Sciences / Biomedicine / Brain / Brain - metabolism / Brain - pathology / Brain slice preparation / Cancer Research / Cerebrospinal fluid / Cognitive ability / Epitopes / Excitability / Female / Hippocampus / Hippocampus - metabolism / Hippocampus - pathology / Humans / Infectious Diseases / Male / Metabolic Diseases / Mice / Molecular Medicine / Neurodegenerative diseases / Neurofibrillary Tangles - metabolism / Neurofibrillary Tangles - pathology / Neuropil / Neurosciences / Other Medical and Health Sciences / Pathology / Phosphorylation / Positron emission / Positron emission tomography / Serine / Serine - metabolism / Synaptic transmission / Tau protein / tau Proteins - cerebrospinal fluid / tau Proteins - chemistry / tau Proteins - metabolism / Threonine