Imaging nanoscopic co-assemblies of α-synuclein and Tau in human samples.
10 affiliations
- 1Department of Chemistry, University of Cambridge, Cambridge, UK. [email protected].
- 2UK Dementia Research Institute at Cambridge, Cambridge, UK. [email protected].
- 3UK Dementia Research Institute at University College London, London, UK.
- 4Department of Chemistry, University of Cambridge, Cambridge, UK.
- 5UK Dementia Research Institute at Cambridge, Cambridge, UK.
- 6Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.
- 7Manchester Centre for Clinical Neurosciences, Salford Royal NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.
- 8St. Thomas' Hospital London, London, UK.
- 9Department of Chemistry, University of Cambridge, Cambridge, UK. [email protected].
- 10UK Dementia Research Institute at Cambridge, Cambridge, UK. [email protected].
Abstract
α-synuclein (αS), amyloid-β (Aβ), and Tau aggregates are hallmarks of many neurodegenerative diseases, yet the prevalence and nature of their nanoscopic co-assemblies remain poorly understood. Here, we adapt a single-molecule pull-down (SiMPull) assay to profile αS, Aβ, and Tau co-assemblies across post-mortem brain tissue homogenates, soluble brain fractions, human serum, cerebrospinal fluid, and saliva. We show that αS-Tau co-assemblies are abundant across all sample matrices, accounting for ~10-70% of total αS aggregates in both Parkinson's disease (PD) and control samples. Notably, αS-Tau co-assemblies in soluble brain fractions from controls exhibit higher Proteinase K (PK) resistance than those from PD cases. Biophysically, Tau accelerates αS aggregation in simple in vitro systems, but this effect is suppressed in complex environments. Together, this work establishes a framework for probing co-assemblies, revealing that αS-Tau species possess heterogeneous biophysical features and are unlikely to act as a single, uniformly toxic species in PD pathology.
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BibTeX
@article{zhang2026imaging,
title = {{Imaging nanoscopic co-assemblies of α-synuclein and Tau in human samples.}},
author = {Yu P Zhang and Amber Wallis and Clara Obensa Bertroli and Cherida Zhang and Melanie Burke and Florence Layburn and Evgeniia Lobanova and Martin Furlepa and Shekhar Kedia and Yuhao Cui and Prasanna Suresh and Woo Suk Yang and Annelies Quaegebeur and Tim Bartels and Caroline H Williams-Gray and David Klenerman},
journal = {Nature communications},
year = {2026},
month = sep,
doi = {10.1038/s41467-026-77728-1},
url = {https://europepmc.org/article/MED/42897149},
note = {CC BY},
}
RIS
TY - JOUR
TI - Imaging nanoscopic co-assemblies of α-synuclein and Tau in human samples.
AU - Yu P Zhang
AU - Amber Wallis
AU - Clara Obensa Bertroli
AU - Cherida Zhang
AU - Melanie Burke
AU - Florence Layburn
AU - Evgeniia Lobanova
AU - Martin Furlepa
AU - Shekhar Kedia
AU - Yuhao Cui
AU - Prasanna Suresh
AU - Woo Suk Yang
AU - Annelies Quaegebeur
AU - Tim Bartels
AU - Caroline H Williams-Gray
AU - David Klenerman
PY - 2026
DA - 2026/09/18
JO - Nature communications
DO - 10.1038/s41467-026-77728-1
UR - https://europepmc.org/article/MED/42897149
AB - α-synuclein (αS), amyloid-β (Aβ), and Tau aggregates are hallmarks of many neurodegenerative diseases, yet the prevalence and nature of their nanoscopic co-assemblies remain poorly understood. Here, we adapt a single-molecule pull-down (SiMPull) assay to profile αS, Aβ, and Tau co-assemblies across post-mortem brain tissue homogenates, soluble brain fractions, human serum, cerebrospinal fluid, and saliva. We show that αS-Tau co-assemblies are abundant across all sample matrices, accounting for ~10-70% of total αS aggregates in both Parkinson's disease (PD) and control samples. Notably, αS-Tau co-assemblies in soluble brain fractions from controls exhibit higher Proteinase K (PK) resistance than those from PD cases. Biophysically, Tau accelerates αS aggregation in simple in vitro systems, but this effect is suppressed in complex environments. Together, this work establishes a framework for probing co-assemblies, revealing that αS-Tau species possess heterogeneous biophysical features and are unlikely to act as a single, uniformly toxic species in PD pathology.
SN - 2041-1723
ER -