ABAD directly links Abeta to mitochondrial toxicity in Alzheimer's disease.
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.
Lustbader
Joyce W
JW
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.
Cirilli
Maurizio
M
Lin
Chang
C
Xu
Hong Wei
HW
Takuma
Kazuhiro
K
Wang
Ning
N
Caspersen
Casper
C
Chen
Xi
X
Pollak
Susan
S
Chaney
Michael
M
Trinchese
Fabrizio
F
Liu
Shumin
S
Gunn-Moore
Frank
F
Lue
Lih-Fen
LF
Walker
Douglas G
DG
Kuppusamy
Periannan
P
Zewier
Zay L
ZL
Arancio
Ottavio
O
Stern
David
D
Yan
Shirley ShiDu
SS
Wu
Hao
H
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
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