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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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3-Hydroxyacyl CoA Dehydrogenases / chemistry
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3-Hydroxyacyl CoA Dehydrogenases / metabolism*
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Aged
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Aged, 80 and over
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Alzheimer Disease / metabolism*
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Amino Acid Sequence
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Amyloid beta-Peptides / chemistry
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Amyloid beta-Peptides / genetics
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Amyloid beta-Peptides / metabolism*
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Animals
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Binding Sites
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Brain / metabolism*
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Brain Chemistry
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Carrier Proteins / chemistry
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Carrier Proteins / metabolism*
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Cells, Cultured
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Cerebral Cortex / chemistry
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Cerebral Cortex / metabolism
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Crystallization
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DNA Fragmentation
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Hippocampus / physiology
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Humans
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Learning
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Memory
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Mice
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Mice, Transgenic
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Microscopy, Confocal
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Microscopy, Immunoelectron
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Mitochondria / chemistry
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Mitochondria / metabolism*
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Models, Molecular
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Molecular Sequence Data
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Mutation
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NAD / metabolism
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Neurons / metabolism
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Protein Binding
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Protein Conformation
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Reactive Oxygen Species / metabolism
Substances
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Amyloid beta-Peptides
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Carrier Proteins
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Reactive Oxygen Species
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NAD
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3-Hydroxyacyl CoA Dehydrogenases
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HSD17B10 protein, human
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Hsd17b10 protein, mouse