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Single‐Molecule Characterization and Super‐Resolution Imaging of Alzheimer's Disease‐Relevant Tau Aggregates in Human Samples

Accepted version
Peer-reviewed

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Authors

Böken, Dorothea 
Cox, Dezerae 
Burke, Melanie 
Lam, Jeff YL 
Katsinelos, Taxiarchis 

Abstract

jats:pHyperphosphorylation and aggregation of the protein tau play key roles in the development of Alzheimer’s disease (AD). While the molecular structure of the filamentous tau aggregates has been determined to atomic resolution, there is far less information available about the smaller, soluble aggregates, which are believed to be more toxic. Traditional techniques are limited to bulk measures and struggle to identify individual aggregates in complex biological samples. To address this, we developed a novel single‐molecule pull‐down‐based assay (MAPTau) to detect and characterize individual tau aggregates in AD and control post‐mortem brain and biofluids. Using MAPTau, we report the quantity, as well as the size and circularity of tau aggregates measured using super‐resolution microscopy, revealing AD‐specific differences in tau aggregate morphology. By adapting MAPTau to detect multiple phosphorylation markers in individual aggregates using two‐color coincidence detection, we derived compositional profiles of the individual aggregates. We find an AD specific phosphorylation profile of tau aggregates with more than 80% containing multiple phosphorylations, compared to 5% in age‐matched non‐AD controls. Our results show that MAPTau is able to identify disease‐specific subpopulations of tau aggregates phosphorylated at different sites, that are invisible to other methods and enable the study of disease mechanisms and diagnosis.</jats:p>

Description

Keywords

3101 Biochemistry and Cell Biology, 31 Biological Sciences, Aging, Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Dementia, Alzheimer's Disease, Acquired Cognitive Impairment, Neurodegenerative, Brain Disorders, 4.1 Discovery and preclinical testing of markers and technologies, 4 Detection, screening and diagnosis, 2.1 Biological and endogenous factors, 2 Aetiology, Neurological

Journal Title

Angewandte Chemie

Conference Name

Journal ISSN

0044-8249
1521-3757

Volume Title

Publisher

Wiley
Sponsorship
Royal Society (RSRP\R\210003)
This work was supported by the UK Dementia Research Institute, which receives its funding from DRI Ltd., funded by the UK Medical Research Council, Alzheimer’s Society, and Alzheimer’s Research. D.C. was supported by the Lady Edith Wolfson Junior Non-Clinical Research Fellowship awarded by the MND Association UK (Cox 971-799). J.Y.L.L. is supported by the Croucher Foundation Limited (Hong Kong). W.A.M and T.K. received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement 116060 (IMPRiND). This Joint Undertaking receives support from the European Union’s Horizon 2020 Research and Innovation Program and EFPIA. This work is supported by the Swiss State Secretariat for Education, Research, and Innovation (SERI) under contract 17.00038. JBR is supported by the Wellcome Trust (103838; 220258), the Medical Research Council (MC_UU_00030/14); JBR and the Cambridge Brain Bank are supported by the NIHR Cambridge Biomedical Research Centre (NIHR203312).