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Templating S100A9 amyloids on Aβ fibrillar surfaces revealed by charge detection mass spectrometry, microscopy, kinetic and microfluidic analyses.

Published version
Peer-reviewed

Type

Article

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Authors

Iashchishyn, Igor A  ORCID logo  https://orcid.org/0000-0002-1691-9025
Fakhouri, Hussein 
Ostojić, Lucija 
Malisauskas, Mantas 

Abstract

The mechanism of amyloid co-aggregation and its nucleation process are not fully understood in spite of extensive studies. Deciphering the interactions between proinflammatory S100A9 protein and Aβ42 peptide in Alzheimer's disease is fundamental since inflammation plays a central role in the disease onset. Here we use innovative charge detection mass spectrometry (CDMS) together with biophysical techniques to provide mechanistic insight into the co-aggregation process and differentiate amyloid complexes at a single particle level. Combination of mass and charge distributions of amyloids together with reconstruction of the differences between them and detailed microscopy reveals that co-aggregation involves templating of S100A9 fibrils on the surface of Aβ42 amyloids. Kinetic analysis further corroborates that the surfaces available for the Aβ42 secondary nucleation are diminished due to the coating by S100A9 amyloids, while the binding of S100A9 to Aβ42 fibrils is validated by a microfluidic assay. We demonstrate that synergy between CDMS, microscopy, kinetic and microfluidic analyses opens new directions in interdisciplinary research.

Description

Keywords

34 Chemical Sciences, Brain Disorders, Aging, Biotechnology, Dementia, Acquired Cognitive Impairment, Bioengineering, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Neurodegenerative, Neurosciences, Alzheimer's Disease, 2.1 Biological and endogenous factors, 1.1 Normal biological development and functioning

Journal Title

Chem Sci

Conference Name

Journal ISSN

2041-6520
2041-6539

Volume Title

11

Publisher

Royal Society of Chemistry (RSC)
Sponsorship
European Research Council (337969)
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