title: ABAD directly links Abeta to mitochondrial toxicity in Alzheimer's disease.
abstract: Mitochondrial dysfunction is a hallmark of beta-amyloid (Abeta)-induced neuronal toxicity in Alzheimer's disease (AD). Here, we demonstrate that Abeta-binding alcohol dehydrogenase (ABAD) is a direct molecular link from Abeta to mitochondrial toxicity. Abeta interacts with ABAD in the mitochondria of AD patients and transgenic mice. The crystal structure of Abeta-bound ABAD shows substantial deformation of the active site that prevents nicotinamide adenine dinucleotide (NAD) binding. An ABAD peptide specifically inhibits ABAD-Abeta interaction and suppresses Abeta-induced apoptosis and free-radical generation in neurons. Transgenic mice overexpressing ABAD in an Abeta-rich environment manifest exaggerated neuronal oxidative stress and impaired memory. These data suggest that the ABAD-Abeta interaction may be a therapeutic target in AD.
authors.affiliation: Center for Reproductive Sciences and Department of Obstetrics and Gynecology, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, New York, NY 10032, USA.
authors.forename: Joyce W
authors.initials: JW
authors.lastname: Lustbader
authors.forename: Maurizio
authors.initials: M
authors.lastname: Cirilli
authors.forename: Chang
authors.initials: C
authors.lastname: Lin
authors.forename: Hong Wei
authors.initials: HW
authors.lastname: Xu
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Takuma
authors.forename: Ning
authors.initials: N
authors.lastname: Wang
authors.forename: Casper
authors.initials: C
authors.lastname: Caspersen
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.forename: Susan
authors.initials: S
authors.lastname: Pollak
authors.forename: Michael
authors.initials: M
authors.lastname: Chaney
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Trinchese
authors.forename: Shumin
authors.initials: S
authors.lastname: Liu
authors.forename: Frank
authors.initials: F
authors.lastname: Gunn-Moore
authors.forename: Lih-Fen
authors.initials: LF
authors.lastname: Lue
authors.forename: Douglas G
authors.initials: DG
authors.lastname: Walker
authors.forename: Periannan
authors.initials: P
authors.lastname: Kuppusamy
authors.forename: Zay L
authors.initials: ZL
authors.lastname: Zewier
authors.forename: Ottavio
authors.initials: O
authors.lastname: Arancio
authors.forename: David
authors.initials: D
authors.lastname: Stern
authors.forename: Shirley ShiDu
authors.initials: SS
authors.lastname: Yan
authors.forename: Hao
authors.initials: H
authors.lastname: Wu
mesh_terms: D015094:3-Hydroxyacyl CoA Dehydrogenases / Q000737:chemistry / Q000378:metabolism*; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism*; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites; D001921:Brain / Q000378:metabolism*; D001923:Brain Chemistry; D002352:Carrier Proteins / Q000737:chemistry / Q000378:metabolism*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000737:chemistry / Q000378:metabolism; D003460:Crystallization; D053938:DNA Fragmentation; D006624:Hippocampus / Q000502:physiology; D006801:Humans; D007858:Learning; D008568:Memory; D051379:Mice; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D016253:Microscopy, Immunoelectron; D008928:Mitochondria / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D009243:NAD / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D002352:Carrier Proteins; D017382:Reactive Oxygen Species; D009243:NAD; D015094:3-Hydroxyacyl CoA Dehydrogenases; C108634:HSD17B10 protein, human; C458480:Hsd17b10 protein, mouse