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.
The authors thank the patients and their families for participating in this research study. We also thank Dr Heather Greer for her help with the acquisition of TEM images. D.K. is supported by Parkinson’s UK (G-1901), Royal Society, Medical Research Council UK (MR/X021874/1), Alzheimer’s Research UK, and UK Dementia Research Institute, which receives its funding from UK DRI Ltd.
C.H.W.-G. is supported by the Medical Research Council UK (MR/W029235/1) and NIHR Cambridge Biomedical Centre (NIHR203312). A.Q. is supported by Aligning Science Across Parkinson’s. The Cambridge Brain Bank is supported by the NIHR Cambridge Biomedical Research Centre (NIHR203312).
The views expressed are those of the authors and not necessarily those of the National Health Service, the NIHR or the Department of Health. T.B. is supported by funding from the Chan Zuckerberg Neurodegeneration Challenge Network (CZI NDCN) Collaborative Pairs, the UK Dementia Research Institute (UKDRI-1011, UKDRI-1207, UKDRI-1209) (which receives its funding from UK DRI Ltd, funded by the UK Medical Research Council, Alzheimer’s Society and Alzheimer’s Research UK), the Michael J. Fox Foundation (QBio 14165992) and the Wellcome Foundation (Discovery Grant 2025).
We additionally thank EPSRC Underpinning Multi-User Equipment Call (EP/P030467/1) for funding the TEM. Department of Chemistry, University of Cambridge, Cambridge, UK Yu P. Zhang, Cherida Zhang, Melanie Burke, Florence Layburn, Evgeniia Lobanova, Martin Furlepa, Shekhar Kedia, Yuhao Cui, Prasanna Suresh, Woo Suk Yang & David Klenerman UK Dementia Research Institute at Cambridge, Cambridge, UK UK Dementia Research Institute at University College London, London, UK Amber Wallis, Clara Obensa Bertroli & Tim Bartels Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK Martin Furlepa, Annelies Quaegebeur & Caroline H.
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