| First Author | Yao J | Year | 2011 |
| Journal | J Neurosci | Volume | 31 |
| Issue | 6 | Pages | 2313-20 |
| PubMed ID | 21307267 | Mgi Jnum | J:169450 |
| Mgi Id | MGI:4941065 | Doi | 10.1523/JNEUROSCI.4717-10.2011 |
| Citation | Yao J, et al. (2011) Inhibition of amyloid-beta (Abeta) peptide-binding alcohol dehydrogenase-Abeta interaction reduces Abeta accumulation and improves mitochondrial function in a mouse model of Alzheimer's disease. J Neurosci 31(6):2313-20 |
| abstractText | Amyloid-beta (Abeta) peptide-binding alcohol dehydrogenase (ABAD), an enzyme present in neuronal mitochondria, exacerbates Abeta-induced cell stress. The interaction of ABAD with Abeta exacerbates Abeta-induced mitochondrial and neuronal dysfunction. Here, we show that inhibition of the ABAD-Abeta 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-Abeta 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-Abeta interaction significantly reduced mitochondrial Abeta accumulation. In parallel, the activity of mitochondrial Abeta-degrading enzyme PreP (presequence peptidase) was enhanced in Tg mAPP mitochondria expressing the ABAD decoy peptide. These data indicate that segregating ABAD from Abeta protects mitochondria/neurons from Abeta toxicity; thus, ABAD-Abeta interaction is an important mechanism underlying Abeta-mediated mitochondrial and neuronal perturbation. Inhibitors of ABAD-Abeta interaction may hold promise as targets for the prevention and treatment of Alzheimer's disease. |
