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O4‐05‐03: Convergence of amyloid‐β and tau pathologies on mitochondria

2010; Wiley; Volume: 6; Issue: 4S_Part_5 Linguagem: Inglês

10.1016/j.jalz.2010.05.490

1552-5279

Anne Eckert, Virginie Rhein, Laurence Ozmen, Bernd Bohrmann, Lars M. Ittner, Christian Czech, Jürgen Götz,

Alzheimer's disease research and treatments

The histopathological characteristics of Alzheimer's disease (AD) are amyloid-ß (Aß) containing plaques and neurofibrillary tangles (NFTs) as well as neuronal and synaptic loss. Until today, the underlying mechanisms of the interplay of plaques and tangles remained unresolved. There is increasing evidence that mitochondrial dysfunction might be a possible link, as revealed by studies in several APP and tau transgenic mouse models. Recently, we examined mitochondrial function in a novel triple transgenic mouse model (pR5/APP/PS2) - triple AD mice - that combines both pathological features of the disease in brain. Comparative, quantitative proteomics (iTRAQ) and mass spectroscopy studies are combined with functional analysis of mitochondria. Mitochondrial respiration is studied with a high-resolution respirometry system (Oxygraph-2k). In addition, enzyme activities of complexes I and IV are determined with spectrophotometric and colorimetric assays. ROS levels, mitochondria membrane potential and ATP levels are determined in cortical brain cells from the mice using fluorescence and bioluminescence assays. We found a massive deregulation of 24 proteins, of which one third were mitochondrial proteins mainly related to complexes I and IV of the oxidative phosphorylation system (OXPHOS). Remarkably, deregulation of complex I was related to tau, whereas deregulation of complex IV was Aß dependent, both at the protein and activity levels. The triple AD mice showed synergistic effects of Aß and tau already at the age of 8 months, resulting in a depolarized mitochondrial membrane potential. At 12 months, the strongest defects on OXPHOS, synthesis of ATP and reactive oxygen species were exhibited in the triple AD mice. Our results suggest that the effects of pathological Aß and tau aggregates converge synergistically on mitochondria in a region-specific manner. These studies may lead to the exploitation of mitochondrial targets for the development of treatments for AD.