Mitochondrial dysfunction: An early event in Alzheimer pathology accumulates with age in AD transgenic mice

Recent evidence suggests mitochondrial dysfunction as a common early pathomechanism in Alzheimer's disease integrating genetic factors related to enhanced amyloid-beta (A beta) production and tau-hyperphosphorylation with aging, as the most relevant sporadic risk factor. To further clarify the synergistic effects of aging and A beta pathology, we used isolated mitochondria of double Swedish and London mutant APP transgenic mice and of non-tg littermates. Pronounced mitochondrial dysfunction in adult Thy-1 APP mice, such as a drop of mitochondrial membrane potential and reduced ATP-levels already appeared at 3 months when elevated intracellular but not extracellular A beta deposits are present. Mitochondrial dysfunction was associated with higher levels of reactive oxygen species, an altered Bcl-xL/Bax ratio and reduction of COX IV activity. We observed significant decreases in state 3 respiration and FCCP-uncoupled respiration in non-tg mice after treatment with extracellular A beta. Similar deficits were seen only in aged Thy-1 APP mice, probably due to compensation within the respiratory chain in young animals. We conclude that A beta dependent mitochondrial dysfunction starts already at 3 months in this AD model before extracellular deposition of A beta and progression accelerates substantially with aging. (C) 2008 Elsevier Inc. All rights reserved.