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Chirality Dependence of Amyloid β Cellular Uptake and a New Mechanistic Perspective
Author(s) -
Dutta Subrata,
Finn Thomas S.,
Kuhn Ariel J.,
Abrams Benjamin,
Raskatov Jevgenij A.
Publication year - 2019
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201800708
Subject(s) - internalization , stereoselectivity , chirality (physics) , chemistry , peptide , amyloid (mycology) , biochemistry , biophysics , enantiomer , computational biology , microbiology and biotechnology , biology , stereochemistry , receptor , inorganic chemistry , chiral symmetry breaking , physics , quantum mechanics , nambu–jona lasinio model , quark , catalysis
Amyloid β is an inherently disordered peptide that can form diverse neurotoxic aggregates, and its 42‐amino‐acid isoform is believed to be the agent responsible for Alzheimer's disease (AD). Cellular uptake of the peptide is a pivotal step for it to be able to exert many of its toxic actions. The cellular uptake process is complex, and numerous competing internalization pathways have been proposed. To date, it remains unclear which of the uptake mechanisms are particularly important for the overall process, and improvement of this understanding is needed, so that better molecular AD therapeutics can be designed. Chirality can be used as a unique tool to study this process, because some of the proposed mechanisms are expected to proceed in stereoselective fashion, whereas others are not. To shed light on this important issue, we synthesized fluorescently labeled enantiomers of amyloid β and quantified their cellular uptake, finding that uptake occurs in stereoselective fashion, with a typical preference for the l stereoisomer of ≈5:1. This suggests that the process is predominantly receptor‐mediated, with likely minor contributions of non‐stereoselective mechanisms.