Single-Molecule Imaging of Individual Amyloid Protein Aggregates in Human Biofluids.

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Horrocks, Mathew H 
Lee, Steven F 
Gandhi, Sonia 
Magdalinou, Nadia K 
Chen, Serene W 

The misfolding and aggregation of proteins into amyloid fibrils characterizes many neurodegenerative disorders such as Parkinson's and Alzheimer's diseases. We report here a method, termed SAVE (single aggregate visualization by enhancement) imaging, for the ultrasensitive detection of individual amyloid fibrils and oligomers using single-molecule fluorescence microscopy. We demonstrate that this method is able to detect the presence of amyloid aggregates of α-synuclein, tau, and amyloid-β. In addition, we show that aggregates can also be identified in human cerebrospinal fluid (CSF). Significantly, we see a twofold increase in the average aggregate concentration in CSF from Parkinson's disease patients compared to age-matched controls. Taken together, we conclude that this method provides an opportunity to characterize the structural nature of amyloid aggregates in a key biofluid, and therefore has the potential to study disease progression in both animal models and humans to enhance our understanding of neurodegenerative disorders.

CSF, Parkinson’s, biomarkers, single-molecule, Aged, Aged, 80 and over, Amyloidogenic Proteins, Benzothiazoles, Circular Dichroism, Diagnostic Imaging, Female, Humans, Male, Microscopy, Atomic Force, Microscopy, Fluorescence, Middle Aged, Parkinson Disease, Thiazoles
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ACS Chem Neurosci
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American Chemical Society (ACS)
The Royal Society (uf120277)
This research study was funded in part by the Wellcome Trust/MRC Joint Call in Neurodegeneration award (WT089698) to the UK Parkinson's Disease Consortium (UKPDC) and the NIHR rare disease translational research collaboration and supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre. We are also grateful to the Augustus Newman and Wolfson Foundations for their support. We thank the Royal Society for the University Research Fellowship of Dr. Steven F. Lee (UF120277).