ABAD directly links Aβ to mitochondrial toxicity in Alzheimer's disease

JW Lustbader, M Cirilli, C Lin, HW Xu, K Takuma, N Wang, C Caspersen, X Chen, S Pollack, M Chaney, F Trinchese, S Liu, Francis James Gunn-Moore, L-F Lue, DG Walker, P Kuppusamy, ZL Zewier, O Arancio, D Stern, SS YanH Wu

Research output: Contribution to journalArticlepeer-review

1154 Citations (Scopus)

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.

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

Keywords

  • BINDING ALCOHOL-DEHYDROGENASE
  • AMYLOID-BETA
  • TRANSGENIC MICE
  • PEPTIDE
  • PROTEIN
  • PATHOGENESIS
  • DYSFUNCTION
  • APOPTOSIS
  • MODEL

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