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Inhibition of Amyloid-beta (A beta) peptide-binding alcohol dehydrogenase-A beta interaction reduces A beta accumulation and improves mitochondrial function in a mouse model of Alzheimer's disease

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Yaoetal2011JnlNeuroscience31Inhibition.pdf (854.9Kb)
Date
09/02/2011
Author
Yao, Jun
Du, Heng
Yan, Shiqiang
Fang, Fang
Wang, Chaodong
Lue, Lih-Fen
Guo, Lan
Chen, Doris
Stern, David M.
Gunn-Moore, Frank J.
Chen, John Xi
Arancio, Ottavio
Yan, Shirley ShiDu
Keywords
Cytochrome-c-oxidase
Oxidative stress
Transgenic mice
Dysfunction
Protein
Brain
Damage
ABAD
Abnormalities
Perturbation
QP Physiology
Metadata
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Abstract
Amyloid- beta (A beta) peptide-binding alcohol dehydrogenase (ABAD), an enzyme present in neuronal mitochondria, exacerbates A beta-induced cell stress. The interaction of ABAD with A beta exacerbates A beta-induced mitochondrial and neuronal dysfunction. Here, we show that inhibition of the ABAD-A beta interaction, using a decoy peptide (DP) in vitro and in vivo, protects against aberrant mitochondrial and neuronal function and improves spatial learning/memory. Intraperitoneal administration of ABAD-DP [fused to the transduction of human immunodeficiency virus 1-transactivator (Tat) protein and linked to the mitochondrial targeting sequence (Mito) (TAT-mito-DP) to transgenic APP mice (Tg mAPP)] blocked formation of ABAD-A beta complex in mitochondria, increased oxygen consumption and enzyme activity associated with the mitochondrial respiratory chain, attenuated mitochondrial oxidative stress, and improved spatial memory. Similar protective effects were observed in Tg mAPP mice overexpressing neuronal ABAD decoy peptide (Tg mAPP/mito-ABAD). Notably, inhibition of the ABAD-A beta interaction significantly reduced mitochondrial A beta accumulation. In parallel, the activity of mitochondrial A beta-degrading enzyme PreP (presequence peptidase) was enhanced in Tg mAPP mitochondria expressing the ABAD decoy peptide. These data indicate that segregating ABAD from A beta protects mitochondria/neurons from A beta toxicity; thus, ABAD-A beta interaction is an important mechanism underlying A beta-mediated mitochondrial and neuronal perturbation. Inhibitors of ABAD-A beta interaction may hold promise as targets for the prevention and treatment of Alzheimer's disease.
Citation
Yao , J , Du , H , Yan , S , Fang , F , Wang , C , Lue , L-F , Guo , L , Chen , D , Stern , D M , Gunn-Moore , F J , Chen , J X , Arancio , O & Yan , S S 2011 , ' Inhibition of Amyloid-beta (A beta) peptide-binding alcohol dehydrogenase-A beta interaction reduces A beta accumulation and improves mitochondrial function in a mouse model of Alzheimer's disease ' , The Journal of Neuroscience , vol. 31 , no. 6 , pp. 2313-2320 . https://doi.org/10.1523/JNEUROSCI.4717-10.2011
Publication
The Journal of Neuroscience
Status
Peer reviewed
DOI
https://doi.org/10.1523/JNEUROSCI.4717-10.2011
ISSN
0270-6474
Type
Journal article
Rights
Copyright (c) 2011 the authors. This article is available under a Creative Commons Attribution-NonCommercial-Share Alike licence http://creativecommons.org/licenses/by-nc-sa/3.0/
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  • University of St Andrews Research
URI
http://hdl.handle.net/10023/2006

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