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Title: Inhibition of the mitochondrial enzyme ABAD restores the amyloid-β-mediated deregulation of estradiol
Authors: Lim Y.-A. 
Grimm A.
Giese M.
Mensah-Nyagan A.G.
Villafranca J.E.
Ittner L.M.
Eckert A.
G?tz J.
Keywords: ag 18051
amyloid beta binding alcohol dehydrogenase
amyloid beta protein[1-42]
enzyme inhibitor
lactate dehydrogenase
mitochondrial enzyme
reactive oxygen metabolite
unclassified drug
3 hydroxyacyl coenzyme A dehydrogenase
amyloid beta protein
amyloid beta protein (1 42)
amyloid beta-protein (1-42)
HSD17B10 protein, human
peptide fragment
reactive oxygen metabolite
Alzheimer disease
controlled study
disorders of mitochondrial functions
down regulation
drug mechanism
enzyme activity
enzyme inhibition
enzyme release
human cell
mitochondrial respiration
neuroblastoma cell
non insulin dependent diabetes mellitus
oxidative stress
protein aggregation
protein function
protein protein interaction
regulatory mechanism
cell line
cell protection
cell respiration
cell survival
drug effect
oxidative phosphorylation
oxygen consumption
protein binding
3-Hydroxyacyl CoA Dehydrogenases
Amyloid beta-Peptides
Cell Line
Cell Respiration
Cell Survival
Enzyme Inhibitors
Islet Amyloid Polypeptide
Oxidative Phosphorylation
Oxygen Consumption
Peptide Fragments
Protein Binding
Reactive Oxygen Species
Issue Date: 2011
Publisher: Public Library of Science
Citation: Lim Y.-A., Grimm A., Giese M., Mensah-Nyagan A.G., Villafranca J.E., Ittner L.M., Eckert A., G?tz J. (2011). Inhibition of the mitochondrial enzyme ABAD restores the amyloid-β-mediated deregulation of estradiol. PLoS ONE 6 (12) : e28887. ScholarBank@NUS Repository.
Abstract: Alzheimer's disease (AD) is a conformational disease that is characterized by amyloid-β (Aβ) deposition in the brain. Aβ exerts its toxicity in part by receptor-mediated interactions that cause down-stream protein misfolding and aggregation, as well as mitochondrial dysfunction. Recent reports indicate that Aβ may also interact directly with intracellular proteins such as the mitochondrial enzyme ABAD (Aβ binding alcohol dehydrogenase) in executing its toxic effects. Mitochondrial dysfunction occurs early in AD, and Aβ's toxicity is in part mediated by inhibition of ABAD as shown previously with an ABAD decoy peptide. Here, we employed AG18051, a novel small ABAD-specific compound inhibitor, to investigate the role of ABAD in Aβ toxicity. Using SH-SY5Y neuroblastoma cells, we found that AG18051 partially blocked the Aβ-ABAD interaction in a pull-down assay while it also prevented the Aβ42-induced down-regulation of ABAD activity, as measured by levels of estradiol, a known hormone and product of ABAD activity. Furthermore, AG18051 is protective against Aβ42 toxicity, as measured by LDH release and MTT absorbance. Specifically, AG18051 reduced Aβ42-induced impairment of mitochondrial respiration and oxidative stress as shown by reduced ROS (reactive oxygen species) levels. Guided by our previous finding of shared aspects of the toxicity of Aβ and human amylin (HA), with the latter forming aggregates in Type 2 diabetes mellitus (T2DM) pancreas, we determined whether AG18051 would also confer protection from HA toxicity. We found that the inhibitor conferred only partial protection from HA toxicity indicating distinct pathomechanisms of the two amyloidogenic agents. Taken together, our results present the inhibition of ABAD by compounds such as AG18051 as a promising therapeutic strategy for the prevention and treatment of AD, and suggest levels of estradiol as a suitable read-out. © 2011 Lim et al.
Source Title: PLoS ONE
ISSN: 19326203
DOI: 10.1371/journal.pone.0028887
Appears in Collections:Staff Publications

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