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E-mail contact: sdy1{at}columbia.edu
Although amyloid-β peptide (Aβ) is the neurotoxic species implicated in the pathogenesis of Alzheimer's disease (AD), mechanisms through which intracellular Aβ impairs cellular properties, resulting in neuronal dysfunction, remain to be clarified. Here we demonstrate that intracellular Aβ is present in mitochondria from brains of transgenic mice with targeted neuronal overexpression of mutant human amyloid precursor protein and AD patients. Aβ progressively accumulates in mitochondria and is associated with diminished enzymatic activity of respiratory chain complexes (III and IV) and a reduction in the rate of oxygen consumption. Importantly, mitochondria-associated Aβ, principally Aβ42, was detected as early as 4 months, before extensive extracellular Aβ deposits. Our studies delineate a new means through which Aβ potentially impairs neuronal energetics, contributing to cellular dysfunction in AD.
Key words: oxidative stress • transgenic mouse model of Alzheimer's disease • respiratory chain enzyme • intracellular Aβ • energy metabolism
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