Lim 2011 PloS One

From Bioblast
Publications in the MiPMap
Lim YA, Grimm A, Giese M, Mensah-Nyagan AG, Villafranca JE, Ittner LM, Eckert A, GΓΆtz J (2011) Inhibition of the mitochondrial enzyme ABAD restores the amyloid-Ξ²-mediated deregulation of estradiol. PloS One 6:e28887.

Β» PMID: 22174920 Open Access

Lim YA, Grimm A, Giese M, Mensah-Nyagan AG, Villafranca JE, Ittner LM, Eckert A, Goetz J (2011) PLoS One

Abstract: Alzheimer's disease (AD) is a conformational disease that is characterized by amyloid-Ξ² (AΞ²) deposition in the brain. AΞ² 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 AΞ² may also interact directly with intracellular proteins such as the mitochondrial enzyme ABAD (AΞ² binding alcohol dehydrogenase) in executing its toxic effects. Mitochondrial dysfunction occurs early in AD, and AΞ²'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 AΞ² toxicity. Using SH-SY5Y neuroblastoma cells, we found that AG18051 partially blocked the AΞ²-ABAD interaction in a pull-down assay while it also prevented the AΞ²42-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 AΞ²42 toxicity, as measured by LDH release and MTT absorbance. Specifically, AG18051 reduced AΞ²42-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 AΞ² 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. β€’ Keywords: Alzheimer's disease (AD), amyloid-Ξ² (AΞ²) deposition, AΞ² binding alcohol dehydrogenase

β€’ O2k-Network Lab: CH Basel Eckert A

Labels: MiParea: Respiration, Pharmacology;toxicology  Pathology: Alzheimer's, Neurodegenerative  Stress:Oxidative stress;RONS  Organism: Human  Tissue;cell: Neuroblastoma  Preparation: Permeabilized cells  Enzyme: Complex I 

Coupling state: LEAK, OXPHOS, ET  Pathway:HRR: Oxygraph-2k 

Cookies help us deliver our services. By using our services, you agree to our use of cookies.