ABAD Directly Links Aβ to Mitochondrial Toxicity in Alzheimer's Disease

Joyce W. Lustbader, Maurizio Cirilli, Chang Lin, Hong Wei Xu, Kazuhiro Takuma, Ning Wang, Casper Caspersen, Xi Chen, Susan Pollak, Michael Chaney, Fabrizio Trinchese, Shumin Liu, Frank Gunn-Moore, Lih Fen Lue, Douglas G. Walker, Periannan Kappasamy, Zay L. Zewier, Ottavio Arancio, David Stern, Shirley Shi Du Yan & 1 others Hao Wu

Research output: Contribution to journalArticle

866 Citations (Scopus)

Abstract

Mitochondrial dysfunction is a hallmark of β-amyloid (Aβ) -induced neuronal toxicity in Alzheimer's disease (AD). Here, we demonstrate that Aβ-binding alcohol dehydrogenase (ABAD) is a direct molecular link from Aβ to mitochondrial toxicity. Aβ interacts with ABAD in the mitochondria of AD patients and transgenic mice. The crystal structure of Aβ-bound ABAD shows substantial deformation of the active site that prevents nicotinamide adenine dinucleotide (NAD) binding. An ABAD peptide specifically inhibits ABAD-Aβ interaction and suppresses Aβ-induced apoptosis and free-radical generation in neurons. Transgenic mice overexpressing ABAD in an Aβ-rich environment manifest exaggerated neuronal oxidative stress and impaired memory. These data suggest that the ABAD-Aβ interaction may be a therapeutic target in AD.

Original languageEnglish (US)
Pages (from-to)448-452
Number of pages5
JournalScience
Volume304
Issue number5669
DOIs
StatePublished - Apr 16 2004

Fingerprint

Alcohol Dehydrogenase
Alzheimer Disease
Transgenic Mice
Amyloid
NAD
Free Radicals
Catalytic Domain
Mitochondria
Oxidative Stress
Apoptosis
Neurons
Peptides

All Science Journal Classification (ASJC) codes

  • General

Cite this

Lustbader, J. W., Cirilli, M., Lin, C., Xu, H. W., Takuma, K., Wang, N., ... Wu, H. (2004). ABAD Directly Links Aβ to Mitochondrial Toxicity in Alzheimer's Disease. Science, 304(5669), 448-452. https://doi.org/10.1126/science.1091230

ABAD Directly Links Aβ to Mitochondrial Toxicity in Alzheimer's Disease. / Lustbader, Joyce W.; Cirilli, Maurizio; Lin, Chang; Xu, Hong Wei; Takuma, Kazuhiro; Wang, Ning; Caspersen, Casper; Chen, Xi; Pollak, Susan; Chaney, Michael; Trinchese, Fabrizio; Liu, Shumin; Gunn-Moore, Frank; Lue, Lih Fen; Walker, Douglas G.; Kappasamy, Periannan; Zewier, Zay L.; Arancio, Ottavio; Stern, David; Yan, Shirley Shi Du; Wu, Hao.

In: Science, Vol. 304, No. 5669, 16.04.2004, p. 448-452.

Research output: Contribution to journalArticle

Lustbader, JW, Cirilli, M, Lin, C, Xu, HW, Takuma, K, Wang, N, Caspersen, C, Chen, X, Pollak, S, Chaney, M, Trinchese, F, Liu, S, Gunn-Moore, F, Lue, LF, Walker, DG, Kappasamy, P, Zewier, ZL, Arancio, O, Stern, D, Yan, SSD & Wu, H 2004, 'ABAD Directly Links Aβ to Mitochondrial Toxicity in Alzheimer's Disease', Science, vol. 304, no. 5669, pp. 448-452. https://doi.org/10.1126/science.1091230
Lustbader JW, Cirilli M, Lin C, Xu HW, Takuma K, Wang N et al. ABAD Directly Links Aβ to Mitochondrial Toxicity in Alzheimer's Disease. Science. 2004 Apr 16;304(5669):448-452. https://doi.org/10.1126/science.1091230
Lustbader, Joyce W. ; Cirilli, Maurizio ; Lin, Chang ; Xu, Hong Wei ; Takuma, Kazuhiro ; Wang, Ning ; Caspersen, Casper ; Chen, Xi ; Pollak, Susan ; Chaney, Michael ; Trinchese, Fabrizio ; Liu, Shumin ; Gunn-Moore, Frank ; Lue, Lih Fen ; Walker, Douglas G. ; Kappasamy, Periannan ; Zewier, Zay L. ; Arancio, Ottavio ; Stern, David ; Yan, Shirley Shi Du ; Wu, Hao. / ABAD Directly Links Aβ to Mitochondrial Toxicity in Alzheimer's Disease. In: Science. 2004 ; Vol. 304, No. 5669. pp. 448-452.
@article{48fc91697a4b41fdb37d42107649583e,
title = "ABAD Directly Links Aβ to Mitochondrial Toxicity in Alzheimer's Disease",
abstract = "Mitochondrial dysfunction is a hallmark of β-amyloid (Aβ) -induced neuronal toxicity in Alzheimer's disease (AD). Here, we demonstrate that Aβ-binding alcohol dehydrogenase (ABAD) is a direct molecular link from Aβ to mitochondrial toxicity. Aβ interacts with ABAD in the mitochondria of AD patients and transgenic mice. The crystal structure of Aβ-bound ABAD shows substantial deformation of the active site that prevents nicotinamide adenine dinucleotide (NAD) binding. An ABAD peptide specifically inhibits ABAD-Aβ interaction and suppresses Aβ-induced apoptosis and free-radical generation in neurons. Transgenic mice overexpressing ABAD in an Aβ-rich environment manifest exaggerated neuronal oxidative stress and impaired memory. These data suggest that the ABAD-Aβ interaction may be a therapeutic target in AD.",
author = "Lustbader, {Joyce W.} and Maurizio Cirilli and Chang Lin and Xu, {Hong Wei} and Kazuhiro Takuma and Ning Wang and Casper Caspersen and Xi Chen and Susan Pollak and Michael Chaney and Fabrizio Trinchese and Shumin Liu and Frank Gunn-Moore and Lue, {Lih Fen} and Walker, {Douglas G.} and Periannan Kappasamy and Zewier, {Zay L.} and Ottavio Arancio and David Stern and Yan, {Shirley Shi Du} and Hao Wu",
year = "2004",
month = "4",
day = "16",
doi = "10.1126/science.1091230",
language = "English (US)",
volume = "304",
pages = "448--452",
journal = "Science",
issn = "0036-8075",
publisher = "American Association for the Advancement of Science",
number = "5669",

}

TY - JOUR

T1 - ABAD Directly Links Aβ to Mitochondrial Toxicity in Alzheimer's Disease

AU - Lustbader, Joyce W.

AU - Cirilli, Maurizio

AU - Lin, Chang

AU - Xu, Hong Wei

AU - Takuma, Kazuhiro

AU - Wang, Ning

AU - Caspersen, Casper

AU - Chen, Xi

AU - Pollak, Susan

AU - Chaney, Michael

AU - Trinchese, Fabrizio

AU - Liu, Shumin

AU - Gunn-Moore, Frank

AU - Lue, Lih Fen

AU - Walker, Douglas G.

AU - Kappasamy, Periannan

AU - Zewier, Zay L.

AU - Arancio, Ottavio

AU - Stern, David

AU - Yan, Shirley Shi Du

AU - Wu, Hao

PY - 2004/4/16

Y1 - 2004/4/16

N2 - Mitochondrial dysfunction is a hallmark of β-amyloid (Aβ) -induced neuronal toxicity in Alzheimer's disease (AD). Here, we demonstrate that Aβ-binding alcohol dehydrogenase (ABAD) is a direct molecular link from Aβ to mitochondrial toxicity. Aβ interacts with ABAD in the mitochondria of AD patients and transgenic mice. The crystal structure of Aβ-bound ABAD shows substantial deformation of the active site that prevents nicotinamide adenine dinucleotide (NAD) binding. An ABAD peptide specifically inhibits ABAD-Aβ interaction and suppresses Aβ-induced apoptosis and free-radical generation in neurons. Transgenic mice overexpressing ABAD in an Aβ-rich environment manifest exaggerated neuronal oxidative stress and impaired memory. These data suggest that the ABAD-Aβ interaction may be a therapeutic target in AD.

AB - Mitochondrial dysfunction is a hallmark of β-amyloid (Aβ) -induced neuronal toxicity in Alzheimer's disease (AD). Here, we demonstrate that Aβ-binding alcohol dehydrogenase (ABAD) is a direct molecular link from Aβ to mitochondrial toxicity. Aβ interacts with ABAD in the mitochondria of AD patients and transgenic mice. The crystal structure of Aβ-bound ABAD shows substantial deformation of the active site that prevents nicotinamide adenine dinucleotide (NAD) binding. An ABAD peptide specifically inhibits ABAD-Aβ interaction and suppresses Aβ-induced apoptosis and free-radical generation in neurons. Transgenic mice overexpressing ABAD in an Aβ-rich environment manifest exaggerated neuronal oxidative stress and impaired memory. These data suggest that the ABAD-Aβ interaction may be a therapeutic target in AD.

UR - http://www.scopus.com/inward/record.url?scp=11144353586&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=11144353586&partnerID=8YFLogxK

U2 - 10.1126/science.1091230

DO - 10.1126/science.1091230

M3 - Article

VL - 304

SP - 448

EP - 452

JO - Science

JF - Science

SN - 0036-8075

IS - 5669

ER -