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. 2009 Nov 6;106(47):20057–20062. doi: 10.1073/pnas.0905529106

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Fig. 1. — High-resolution respiratory system reveals a heightened defect in the mitochondrial OXPHOS from brains of ^tripleAD mice. Measurement of oxygen (O₂) flux and consumption in freshly isolated mitochondria from cortical brains of age-matched wild-type, APP/PS2, and ^tripleAD mice. After detection of endogenous respiration (mito), glutamate+malate (g/m) were added to induce state 4 respiration. ADP stimulated state 3 respiration. After determining coupled respiration, FCCP was added and the maximal respiratory capacity measured in the absence of a proton gradient. Cytochrome c (cyt c) demonstrated mitochondrial membrane integrity. To inhibit activities of complexes I–III, rotenone (rot) and antimycine A (AA) were added. Complex IV activity was stimulated by ascorbate/TMPD (A/T) before terminating mitochondrial respiration by adding sodium azide (azide). O₂ consumption was normalized to the corresponding citrate synthase (CS) activity. (A) Representative diagrams of O₂ flux and consumption in mitochondria from 12-month-old wild-type, APP/PS2, and ^tripleAD mice in response to titrated substrates and inhibitors of mitochondrial complexes. (B) RCR3/4 (state3/state4 ratio) representing the mitochondrial coupling state was reduced in 8- and 12-month-old APP/PS2 and ^tripleAD mice. (C) ETS/ROX ratio, which yields an index of the maximum oxygen consumption capacity of the electron transport system (ETS) relative to the magnitude of residual oxygen consumption (ROX), was reduced in 8- and 12-month-old APP/PS2 and ^tripleAD mice compared with age-matched wild-type mitochondria. (D) Two-way ANOVA revealed a significant effect of the transgene on the respiratory rates of mitochondria between 8-month-old wild-type and APP/PS2 mice (P < 0.001). (E) No difference was observed in respiration between 8-month-old APP/PS2 and ^tripleAD mice. (F) At 12 months of age, respiration differed again significantly between wild-type and APP/PS2 (P < 0.001) and (G) between APP/PS2 and ^tripleAD mice (P < 0.001). (B and C) One-way ANOVA post hoc Tukey's. (D–G) Two-way ANOVA post hoc Bonferroni. *, P < 0.05; **, P < 0.01; ***, P < 0.001 vs. wild-type; ⁺⁺, P < 0.01; ⁺⁺⁺, P < 0.001 vs. APP/PS2 (n = 7–12 animals/group).