Mitochondrial Toxicity in Alzheimer's Disease

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Science  16 Apr 2004:
Vol. 304, Issue 5669, pp. 356
DOI: 10.1126/science.304.5669.356j

Aggregates of amyloid beta (Aβ) protein are a characteristic of Alzheimer's disease (AD), and these aggregates are toxic to neurons. Mitochondrial dysfunction is a hallmark of this neuronal toxicity. Now Lustbader et al. (p. 448) show that Aβ interacts directly with Aβ-binding alcohol dehydrogenase (ABAD) in the mitochondria of AD patients and in transgenic mice. A crystal structure shows that binding of Aβ prevents nicotinamide adenine dinucleotide binding to ABAD, which results in a loss of activity of ABAD and promotes leakage of reactive oxygen species, mitochondrial dysfunction, and cell death. Thus, the interaction of Aβ with ABAD in mitochondria may play a role in the pathogenesis of AD.

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