The Major Components of Cerebrospinal Fluid Dictate the Characteristics of Inhibitors against Amyloid-Beta Aggregation

Sakalauskas, Andrius; Ziaunys, Mantas; Snieckute, Ruta; Janoniene, Agne; Veiveris, Dominykas; Zvirblis, Mantas; Dudutiene, Virginija; Smirnovas, Vytautas

doi:10.3390/ijms24065991

Open AccessArticle

The Major Components of Cerebrospinal Fluid Dictate the Characteristics of Inhibitors against Amyloid-Beta Aggregation

by

Andrius Sakalauskas

^*

,

Mantas Ziaunys

,

Ruta Snieckute

,

Agne Janoniene

,

Dominykas Veiveris

,

Mantas Zvirblis

,

Virginija Dudutiene

and

Vytautas Smirnovas

^*

Institute of Biotechnology, Life Sciences Center, Vilnius University, LT-10257 Vilnius, Lithuania

^*

Authors to whom correspondence should be addressed.

Int. J. Mol. Sci. 2023, 24(6), 5991; https://doi.org/10.3390/ijms24065991

Submission received: 27 February 2023 / Revised: 20 March 2023 / Accepted: 21 March 2023 / Published: 22 March 2023

(This article belongs to the Special Issue Recent Advances in Protein Misfolding and Aggregation in Neurodegenerative Disorders)

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Abstract

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.

Keywords: protein aggregation; amyloid-beta; inhibition; EGCG; VR16-09; aggregation kinetics; near-physiological conditions

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MDPI and ACS Style

Sakalauskas, A.; Ziaunys, M.; Snieckute, R.; Janoniene, A.; Veiveris, D.; Zvirblis, M.; Dudutiene, V.; Smirnovas, V. The Major Components of Cerebrospinal Fluid Dictate the Characteristics of Inhibitors against Amyloid-Beta Aggregation. Int. J. Mol. Sci. 2023, 24, 5991. https://doi.org/10.3390/ijms24065991

AMA Style

Sakalauskas A, Ziaunys M, Snieckute R, Janoniene A, Veiveris D, Zvirblis M, Dudutiene V, Smirnovas V. The Major Components of Cerebrospinal Fluid Dictate the Characteristics of Inhibitors against Amyloid-Beta Aggregation. International Journal of Molecular Sciences. 2023; 24(6):5991. https://doi.org/10.3390/ijms24065991

Chicago/Turabian Style

Sakalauskas, Andrius, Mantas Ziaunys, Ruta Snieckute, Agne Janoniene, Dominykas Veiveris, Mantas Zvirblis, Virginija Dudutiene, and Vytautas Smirnovas. 2023. "The Major Components of Cerebrospinal Fluid Dictate the Characteristics of Inhibitors against Amyloid-Beta Aggregation" International Journal of Molecular Sciences 24, no. 6: 5991. https://doi.org/10.3390/ijms24065991

APA Style

Sakalauskas, A., Ziaunys, M., Snieckute, R., Janoniene, A., Veiveris, D., Zvirblis, M., Dudutiene, V., & Smirnovas, V. (2023). The Major Components of Cerebrospinal Fluid Dictate the Characteristics of Inhibitors against Amyloid-Beta Aggregation. International Journal of Molecular Sciences, 24(6), 5991. https://doi.org/10.3390/ijms24065991

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The Major Components of Cerebrospinal Fluid Dictate the Characteristics of Inhibitors against Amyloid-Beta Aggregation

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