Mitochondrial failure precedes amyloid beta plaques deposition in APP transgenic mice

Mitochondrial dysfunction has been identified in neurodegenertive disorders including Alzheimer's disease (AD), where accumulation of amyloid beta (A beta) and oxidative stress seem to play central roles in the pathogenesis, by probably directly leading to mitochondrial dysfunction. In order to study the in vivo effect of A beta load during aging, we evaluated the mitochondrial function of brain cells from transgenic (tg) mice bearing mutant amyloid precursor protein (APP, Swedish and London mutation) and non-tg littermate control animals (non-tg) at different ages (1.5, 3, and 6 months). TgAPP mice exhibit onset of A beta plaques at an age of 6 months, but intracellular A (beta) load is already increased at the age of 3 months. Basal mitochondrial transmembrane potential was already decreased in APPtg mice at an age of 1.5 months and decreased further with aging. ATP levels were significantly reduced in tgAPP mice at an age of 3 months compared to age-matched non-tg control mice. Interestingly, cytochrome c oxidase activity was markedly reduced in tgAPP mice at an age of 1.5 and 3 months. The difference was less pronounced at an age of 6 months. In addition, the Bcl-xL/Bax ratio was significantly reduced in brains from tgAPP mice possibly contributing to the mitochondrial dysfunction in tgAPP mice. Taken together, our results indicate that mitochondrial dysfunction is exacerbated by the presence of intracellular A beta as a very early event during pathogenesis.