Modulation of Aβ42 Aggregation Kinetics and Pathway by Low-Molecular-Weight Inhibitors

Marie-Theres Hutchison; Giovanni Bellomo; Alexey Cherepanov; Elke Stirnal; Boris Fürtig; Christian Richter; Verena Linhard; Elina Gurewitsch; Moreno Lelli; Nina Morgner; Thomas Schrader; Harald Schwalbe

doi:10.1002/cbic.202200760

Modulation of Aβ42 Aggregation Kinetics and Pathway by Low-Molecular-Weight Inhibitors

Chembiochem. 2023 Apr 3;24(7):e202200760. doi: 10.1002/cbic.202200760. Epub 2023 Mar 2.

Authors

Affiliations

¹ Institute for Organic Chemistry and Chemical Biology Center for Biomolecular Magnetic Resonance (BMRZ), Goethe University Frankfurt, Max-von-Laue-Str. 7, 60438, Frankfurt/Main, Germany.
² Laboratory of Clinical Neurochemistry Department of Medicine and Surgery, University of Perugia, Piazzale Lucio Severi 1/8, 06132, Perugia, Italy.
³ Chemistry Department, University of Florence, Via della Lastruccia 3, 50019, Sesto Fiorentino, Italy.
⁴ Magnetic Resonance Center (CERM/CIRMMP), University of Florence, Via Luigi Sacconi 6, 50019, Sesto Fiorentino, Italy.
⁵ Institute for Physical and Theoretical Chemistry, Goethe University Frankfurt, Max-von-Laue-Str. 9, 60438, Frankfurt/Main, Germany.
⁶ Institute for Organic Chemistry, University of Duisburg-Essen, Universitätsstrasse 7, 45117, Essen, Germany.

PMID: 36652672
DOI: 10.1002/cbic.202200760

Abstract

The aggregation of amyloid-β 42 (Aβ42) is directly related to the pathogenesis of Alzheimer's disease. Here, we have investigated the early stages of the aggregation process, during which most of the cytotoxic species are formed. Aβ42 aggregation kinetics, characterized by the quantification of Aβ42 monomer consumption, were tracked by real-time solution NMR spectroscopy (RT-NMR) allowing the impact that low-molecular-weight (LMW) inhibitors and modulators exert on the aggregation process to be analysed. Distinct differences in the Aβ42 kinetic profiles were apparent and were further investigated kinetically and structurally by using thioflavin T (ThT) and transmission electron microscopy (TEM), respectively. LMW inhibitors were shown to have a differential impact on early-state aggregation. Insight provided here could direct future therapeutic design based on kinetic profiling of the process of fibril formation.

Keywords: NMR spectroscopy; aggregation; amyloid beta-peptides; inhibitors; kinetics.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alzheimer Disease* / drug therapy
Alzheimer Disease* / metabolism
Amyloid beta-Peptides* / metabolism
Humans
Kinetics
Peptide Fragments / chemistry

Substances

amyloid beta-protein (1-42)
Amyloid beta-Peptides
Peptide Fragments