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

Abstract

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.

Specific Binding of Alzheimer’s Aβ Peptides to Extracellular Vesicles

“…Many elegant studies [10,11,14,15,18,23,33,46,[53][54][55], using techniques that include Western blotting, transcriptomics, proteomics, ELISA, PCR, immunohistochemistry, immunocytochemistry, and electron microscopy, have been directed at the understanding of the role of extracellular vesicles in the pathology of AD and in particular at the significance of Aβ-EV associations. While there is agreement that exosomes carry Aβ, there is a wide range of views on whether the purpose of this association is physiologically beneficial or pathological, the conclusions of which are also dependent on whether the authors of these works consider Aβ in its fibrillar form to be more toxic or protective [59][60][61][62][63][64][65][66][67][68][69][70][71][72][73][74][75][76]. Research points to many potentials.…”