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Amyloidogenic Nanoplaques in Blood Serum of Patients with Alzheimers Disease Revealed by Time-Resolved Thioflavin T Fluorescence Intensity Fluctuation Analysis
Karolinska Inst, Sweden.
Karolinska Inst, Sweden.
Stockholm Univ, Sweden; NICPB, Estonia.
Region Östergötland, Local Health Care Services in East Östergötland, Department of Internal Medicine in Norrköping.
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2019 (English)In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 68, no 2, p. 571-582Article in journal (Refereed) Published
Abstract [en]

Background: Biomarkers are central to current research on molecular mechanisms underlying Alzheimers disease (AD). Their further development is of paramount importance for understanding pathophysiological processes that eventually lead to disease onset. Biomarkers are also crucial for early disease detection, before clinical manifestation, and for development of new disease modifying therapies. Objective: The overall aim of this work is to develop a minimally invasive method for fast, ultra-sensitive and cost-effective detection of structurally modified peptide/protein self-assemblies in the peripheral blood and in other biological fluids. Specifically, we focus here on using this method to detect structured amyloidogenic oligomeric aggregates in the blood serum of apparently healthy individuals and patients in early AD stage, and measure their concentration and size. Methods: Time-resolved detection of Thioflavin T (ThT) fluorescence intensity fluctuations in a sub-femtoliter observation volume element was used to identify in blood serum ThT-active structured amyloidogenic oligomeric aggregates, hereafter called nanoplaques, and measure with single-particle sensitivity their concentration and size. Results: The concentration and size of structured amyloidogenic nanoplaques are significantly higher in the blood serum of individuals diagnosed with AD than in control subjects. Conclusion: A new method with the ultimate, single-particle sensitivity was successfully developed. The proposed approach neither relies on the use of immune-based probes, nor on the use of radiotracers, signal-amplification or protein separation techniques, and provides a minimally invasive test for fast and cost-effective early determination of structurally modified peptides/proteins in the peripheral blood, as shown here, but also in other biological fluids.

Place, publisher, year, edition, pages
IOS PRESS , 2019. Vol. 68, no 2, p. 571-582
Keywords [en]
Alzheimers disease; amyloidogenic aggregates; beta-pleated sheet; blood serum; early diagnosis; florescence intensity fluctuation analysis; fluorescence correlation spectroscopy; single-molecule sensitivity; Thioflavin T
National Category
Clinical Laboratory Medicine
Identifiers
URN: urn:nbn:se:liu:diva-156403DOI: 10.3233/JAD-181144ISI: 000462875000015PubMedID: 30814355OAI: oai:DiVA.org:liu-156403DiVA, id: diva2:1305707
Note

Funding Agencies|Knut and Alice Wallenberg Foundation [KAW 2011.0218]; Swedish Research Council [2016-01922]; Foundation for Strategic Research [SBE13-0115]; Olav Thon Foundation; Magnus Bergvalls Foundation [2016-01615]

Available from: 2019-04-18 Created: 2019-04-18 Last updated: 2019-04-18

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