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A rationally designed small molecule for identifying an in vivo link between metal-amyloid-? complexes and the pathogenesis of Alzheimer's disease.

ABSTRACT: Multiple factors, including amyloid-? (A?), metals, and reactive oxygen species (ROS), are involved in the development of Alzheimer's disease (AD). Metal ions can interact with A? species generating toxic oligomers and ROS in vitro; however, the involvement of metal-A? complexes in AD pathology in vivo remains unclear. To solve this uncertainty, we have developed a chemical tool (L2-b) that specifically targets metal-A? complexes and modulates their reactivity (i.e., metal-A? aggregation, toxic oligomer formation, and ROS production). Through the studies presented herein, we demonstrate that L2-b is able to specifically interact with metal-A? complexes over metal-free A? analogues, redirect metal-A? aggregation into off-pathway, nontoxic less structured A? aggregates, and diminish metal-A?-induced ROS production, overall mitigating metal-A?-triggered toxicity, confirmed by multidisciplinary approaches. L2-b is also verified to enter the brain in vivo with relative metabolic stability. Most importantly, upon treatment of 5XFAD AD mice with L2-b, (i) metal-A? complexes are targeted and modulated in the brain; (ii) amyloid pathology is reduced; and (iii) cognition deficits are significantly improved. To the best of our knowledge, by employing an in vivo chemical tool specifically prepared for investigating metal-A? complexes, we report for the first time experimental evidence that metal-A? complexes are related directly to AD pathogenesis.

SUBMITTER: Beck MW

PROVIDER: S-EPMC5494539 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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A rationally designed small molecule for identifying an in vivo link between metal-amyloid-β complexes and the pathogenesis of Alzheimer's disease.

Beck Michael W MW Oh Shin Bi SB Kerr Richard A RA Lee Hyuck Jin HJ Kim So Hee SH Kim Sujeong S Jang Milim M Ruotolo Brandon T BT Lee Joo-Yong JY Lim Mi Hee MH

Chemical science 20150127 3

Multiple factors, including amyloid-β (Aβ), metals, and reactive oxygen species (ROS), are involved in the development of Alzheimer's disease (AD). Metal ions can interact with Aβ species generating toxic oligomers and ROS in vitro; however, the involvement of metal-Aβ complexes in AD pathology in vivo remains unclear. To solve this uncertainty, we have developed a chemical tool (L2-b) that specifically targets metal-Aβ complexes and modulates their reactivity (i.e., ...[more]

PMID: 28706643

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Project description:Electrostatic interactions, and specifically π-interactions play a significant role in the liquid-liquid phase separation of proteins and formation of membraneless organelles/or biological condensates. Sequence patterning of peptides allows creating protein-like structures and controlling the chemistry and interactions of the mimetic molecules. A library of oppositely charged polypeptides was designed and synthesized to investigate the role of π-interactions on phase separation and secondary structures of polyelectrolyte complexes. Phenylalanine was chosen as the π-containing residue and was used together with lysine or glutamic acid in the design of positively or negatively charged sequences. The effect of charge density and also the substitution of fluorine on the phenylalanine ring, known to disrupt π-interactions, were investigated. Characterization analysis using MALDI-TOF mass spectroscopy, H NMR, and circular dichroism (CD) confirmed the molecular structure and chiral pattern of peptide sequences. Despite an alternating sequence of chirality previously shown to promote liquid-liquid phase separation, complexes appeared as solid precipitates, suggesting strong interactions between the sequence pairs. The secondary structures of sequence pairs showed the formation of hydrogen-bonded structures with a β-sheet signal in FTIR spectroscopy. The presence of fluorine decreased hydrogen bonding due to its inhibitory effect on π-interactions. π-interactions resulted in enhanced stability of complexes against salt, and higher critical salt concentrations for complexes with more π-containing amino acids. Furthermore, UV-vis spectroscopy showed that sequences containing π-interactions and increased charge density encapsulated a small charged molecule with π-bonds with high efficiency. These findings highlight the interplay between ionic, hydrophobic, hydrogen bonding, and π-interactions in polyelectrolyte complex formation and enhance our understanding of phase separation phenomena in protein-like structures.

Dataset Information

A rationally designed small molecule for identifying an in vivo link between metal-amyloid-? complexes and the pathogenesis of Alzheimer's disease.

Publications

A rationally designed small molecule for identifying an <i>in vivo</i> link between metal-amyloid-β complexes and the pathogenesis of Alzheimer's disease.

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