Stereochemistry-activity relationship of ceramide-induced exosome production to clear amyloid-β in Alzheimer's disease.

Autor: Abdelrasoul M; Graduate School of Life Science, Hokkaido University, Sapporo, Japan.; Department of Medicinal Chemistry, Faculty of Pharmacy, Assiut University, Assiut, Egypt., Yuyama K; Faculty of Advanced Life Science, Hokkaido University, Sapporo, Japan., Swamy MMM; Graduate School of Life Science, Hokkaido University, Sapporo, Japan.; Faculty of Advanced Life Science, Hokkaido University, Sapporo, Japan., Murai Y; Graduate School of Life Science, Hokkaido University, Sapporo, Japan.; Faculty of Advanced Life Science, Hokkaido University, Sapporo, Japan., Monde K; Graduate School of Life Science, Hokkaido University, Sapporo, Japan.; Faculty of Advanced Life Science, Hokkaido University, Sapporo, Japan.
Jazyk: angličtina
Zdroj: Chirality [Chirality] 2023 Sep; Vol. 35 (9), pp. 577-585. Date of Electronic Publication: 2023 Apr 13.
DOI: 10.1002/chir.23568
Abstrakt: Stereochemistry has a substantial impact on the biological activity of various drugs. We investigated the role of stereochemistry of ceramides in inducing the production of exosomes, a type of extracellular vesicle, from neuronal cells, with a potential benefit in improving the clearance of amyloid-β (Aβ), a causal agent of Alzheimer's disease. A stereochemical library of diverse ceramides with different tail lengths was synthesized with the purpose of varying stereochemistry (D-erythro: DE, D-threo: DT, L-erythro: LE, L-threo: LT) and hydrophobic tail length (C6, C16, C18, C24). The exosome levels were quantified using TIM4-based exosome enzyme-linked immunosorbent assay after concentrating the conditioned medium using centrifugal filter devices. The results revealed a pivotal role of stereochemistry in determining the biological activity of ceramide stereoisomers, with the superiority of those based on DE and DT stereochemistry with C16 and C18 tails, which demonstrated significantly higher exosome production, without a significant change in the particle size of the released exosomes. In transwell experiments with Aβ-expressed neuronal and microglial cells, DE- and DT-ceramides with C16 and C18 tails significantly decreased extracellular Aβ levels. The results reported here are promising in the design of non-classic therapies for the treatment of Alzheimer's disease.
(© 2023 Wiley Periodicals LLC.)
Databáze: MEDLINE
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