Inhibition of the mitochondrial enzyme ABAD restores the amyloid-β-mediated deregulation of estradiol

Lim, Yun-An, Grimm, Amandine, Giese, Maria, Mensah-Nyagan, Ayikoe Guy, Villafranca, J. Ernest, Ittner, Lars M., Eckert, Anne and Gotz, Jurgen (2011) Inhibition of the mitochondrial enzyme ABAD restores the amyloid-β-mediated deregulation of estradiol. PLoS ONE, 6 12: e28887.1-e28887.12. doi:10.1371/journal.pone.0028887


Author Lim, Yun-An
Grimm, Amandine
Giese, Maria
Mensah-Nyagan, Ayikoe Guy
Villafranca, J. Ernest
Ittner, Lars M.
Eckert, Anne
Gotz, Jurgen
Title Inhibition of the mitochondrial enzyme ABAD restores the amyloid-β-mediated deregulation of estradiol
Journal name PLoS ONE   Check publisher's open access policy
ISSN 1932-6203
Publication date 2011-12-01
Year available 2011
Sub-type Article (original research)
DOI 10.1371/journal.pone.0028887
Open Access Status DOI
Volume 6
Issue 12
Start page e28887.1
End page e28887.12
Total pages 12
Place of publication San Francisco, United States
Publisher Public Library of Science (PLoS)
Language eng
Formatted 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.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: Queensland Brain Institute Publications
 
Versions
Version Filter Type
Citation counts: TR Web of Science Citation Count  Cited 21 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 18 times in Scopus Article | Citations
Google Scholar Search Google Scholar
Created: Wed, 26 Feb 2014, 18:26:02 EST by System User on behalf of Queensland Brain Institute