Title The major components of cerebrospinal fluid dictate the characteristics of inhibitors against amyloid-beta aggregation /
Authors Sakalauskas, Andrius ; Žiaunys, Mantas ; Sniečkutė, Rūta ; Janonienė, Agnė ; Veiveris, Dominykas ; Žvirblis, Mantas ; Dudutienė, Virginija ; Smirnovas, Vytautas
DOI 10.3390/ijms24065991
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Is Part of International journal of molecular sciences.. Basel : MDPI. 2023, vol. 24, iss. 6, art. no. 5991, p. [1-12].. ISSN 1661-6596. eISSN 1422-0067
Keywords [eng] aggregation kinetics ; amyloid-beta ; EGCG ; inhibition ; near-physiological conditions ; protein aggregation ; VR16-09
Abstract [eng] The main pathological hallmark of Alzheimer’s disease (AD) is the aggregation of amyloid-β into amyloid fibrils, leading to a neurodegeneration cascade. The current medications are far from sufficient to prevent the onset of the disease, hence requiring more research to find new alternative drugs for curing AD. In vitro inhibition experiments are one of the primary tools in testing whether a molecule may be potent to impede the aggregation of amyloid-beta peptide (Aβ42). However, kinetic experiments in vitro do not match the mechanism found when aggregating Aβ42 in cerebrospinal fluid. The different aggregation mechanisms and the composition of the reaction mixtures may also impact the characteristics of the inhibitor molecules. For this reason, altering the reaction mixture to resemble components found in cerebrospinal fluid (CSF) is critical to partially compensate for the mismatch between the inhibition experiments in vivo and in vitro. In this study, we used an artificial cerebrospinal fluid that contained the major components found in CSF and performed Aβ42 aggregation inhibition studies using oxidized epigallocatechin-3-gallate (EGCG) and fluorinated benzenesulfonamide VR16-09. This led to a discovery of a complete turnaround of their inhibitory characteristics, rendering EGCG ineffective while significantly improving the efficacy of VR16-09. HSA was the main contributor in the mixture that significantly increased the anti-amyloid characteristics of VR16-09.
Published Basel : MDPI
Type Journal article
Language English
Publication date 2023
CC license CC license description