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

Jun Yao, Heng Du, Shiqiang Yan, Fang Fang, Chaodong Wang, Lih-Fen Lue, Lan Guo, Doris Chen, David M. Stern, Frank J. Gunn-Moore, John Xi Chen, Ottavio Arancio, Shirley ShiDu Yan

Research output: Contribution to journalArticlepeer-review

132 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2313-2320
Number of pages8
JournalThe Journal of Neuroscience
Volume31
Issue number6
DOIs
Publication statusPublished - 9 Feb 2011

Keywords

  • Cytochrome-c-oxidase
  • Oxidative stress
  • Transgenic mice
  • Dysfunction
  • Protein
  • Brain
  • Damage
  • ABAD
  • Abnormalities
  • Perturbation

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