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Lim, Mi Hee
MetalloNeuroChemistry Lab (MNCL)
Research Interests
  • Neurodegenerative disease, small molecule design, network between metal, proteins, and ROS

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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

Cited 6 times inthomson ciCited 4 times inthomson ci
Title
A rationally designed small molecule for identifying an in vivo link between metal-amyloid-β complexes and the pathogenesis of Alzheimer's disease
Author
Beck, Michael W.Oh, Shin BiKerr, Richard A.Lee, Hyuck JinKim, So HeeKim, SujeongJang, MilimRuotolo, Brandon T.Lee, Joo-YongLim, Mi Hee
Issue Date
2015-03
Publisher
ROYAL SOC CHEMISTRY
Citation
CHEMICAL SCIENCE, v.6, no.3, pp.1879 - 1886
Abstract
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., metal-Aβ aggregation, toxic oligomer formation, and ROS production). Through the studies presented herein, we demonstrate that L2-b is able to specifically interact with metal-Aβ complexes over metal-free Aβ analogues, redirect metal-Aβ aggregation into off-pathway, nontoxic less structured Aβ aggregates, and diminish metal-Aβ-induced ROS production, overall mitigating metal-Aβ-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-Aβ 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-Aβ complexes, we report for the first time experimental evidence that metal-Aβ complexes are related directly to AD pathogenesis.
URI
https://scholarworks.unist.ac.kr/handle/201301/10923
URL
http://pubs.rsc.org/en/Content/ArticleLanding/2015/SC/C4SC03239J#!divAbstract
DOI
10.1039/c4sc03239j
ISSN
2041-6520
Appears in Collections:
PHY_Journal Papers
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