Mitochondrial Aβ:: a potential focal point for neuronal metabolic dysfunction in Alzheimer's disease

Although amyloid-beta peptide (A beta) is the neurotoxic species implicated in the pathogenesis of Alzheimer's disease ( AD), mechanisms through which intracellular A beta impairs cellular properties, resulting in neuronal dysfunction, remain to be clarified. Here we demonstrate that intracellular A beta is present in mitochondria from brains of transgenic mice with targeted neuronal overexpression of mutant human amyloid precursor protein and AD patients. A beta 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 A beta, principally A beta 42, was detected as early as 4 months, before extensive extracellular A beta deposits. Our studies delineate a new means through which A beta potentially impairs neuronal energetics, contributing to cellular dysfunction in AD.