title: 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.
abstract: Amyloid-β (Aβ) peptide-binding alcohol dehydrogenase (ABAD), an enzyme present in neuronal mitochondria, exacerbates Aβ-induced cell stress. The interaction of ABAD with Aβ exacerbates Aβ-induced mitochondrial and neuronal dysfunction. Here, we show that inhibition of the ABAD-Aβ 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-Aβ 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-Aβ interaction significantly reduced mitochondrial Aβ accumulation. In parallel, the activity of mitochondrial Aβ-degrading enzyme PreP (presequence peptidase) was enhanced in Tg mAPP mitochondria expressing the ABAD decoy peptide. These data indicate that segregating ABAD from Aβ protects mitochondria/neurons from Aβ toxicity; thus, ABAD-Aβ interaction is an important mechanism underlying Aβ-mediated mitochondrial and neuronal perturbation. Inhibitors of ABAD-Aβ interaction may hold promise as targets for the prevention and treatment of Alzheimer's disease.
authors.affiliation: Department of Pathology, Taub Institute for Research on Alzheimer Disease and the Aging Brain, Columbia University, New York, New York 10032, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Yao
authors.forename: Heng
authors.initials: H
authors.lastname: Du
authors.forename: Shiqiang
authors.initials: S
authors.lastname: Yan
authors.forename: Fang
authors.initials: F
authors.lastname: Fang
authors.forename: Chaodong
authors.initials: C
authors.lastname: Wang
authors.forename: Lih-Fen
authors.initials: LF
authors.lastname: Lue
authors.forename: Lan
authors.initials: L
authors.lastname: Guo
authors.forename: Doris
authors.initials: D
authors.lastname: Chen
authors.forename: David M
authors.initials: DM
authors.lastname: Stern
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gunn Moore
authors.forename: John
authors.initials: J
authors.lastname: Xi Chen
authors.forename: Ottavio
authors.initials: O
authors.lastname: Arancio
authors.forename: Shirley ShiDu
authors.initials: SS
authors.lastname: Yan
mesh_terms: D015094:3-Hydroxyacyl CoA Dehydrogenases / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D000110:Acetylcholinesterase / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000494:pharmacology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D001921:Brain / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure*; D004195:Disease Models, Animal; D014450:Electron Transport Complex III / Q000378:metabolism; D003576:Electron Transport Complex IV / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D058851:GPI-Linked Proteins / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D047468:Immunoprecipitation / Q000379:methods; D008568:Memory / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D013028:Space Perception / Q000187:drug effects / Q000502:physiology
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D058851:GPI-Linked Proteins; D017382:Reactive Oxygen Species; D015094:3-Hydroxyacyl CoA Dehydrogenases; C108634:HSD17B10 protein, human; D003576:Electron Transport Complex IV; D000110:Acetylcholinesterase; C548246:Ache protein, rat; D014450:Electron Transport Complex III