3). Indeed, our group demonstrated a mitochondrial dysfunction in a novel triple transgenic mouse model (pR5/APPSw/PS2 N141I) – tripleAD mice – using proteomics followed by functional validation [9]. Notably, deregulation of complex I was found to be tau-dependent, while deregulation of complex IV was A??-dependent, at both selleck Oligomycin A the protein and activity level (Figure ?(Figure5).5). Whereas down-regulation of several subunits of complex I was observed in tripleAD mice compared to both pR5 and APPSw/PS2 mice, deregulation of several subunits of complex V was seen in tripleAD mice compared to pR5 mice but not compared to APPSw/PS2 mice (Figure ?(Figure4).4). The convergent effects of A?? and tau led already at the age of 8 months to depolarized mitochondrial membrane potential in tripleAD mice.

Additionally, we found that age-related oxidative stress at 12 months of age may exaggerate the disturbances in the respiratory system and synthesis of ATP and, in turn, take part in the vicious cycle that finally leads to cell death. Figure 5 Impairment of the electron transport chain in Alzheimer’s disease. Complexes I (NADH:ubiquinone oxidoreductase) and II (succinate dehydrogenase, belongs to the tricarboxylic acid (TCA) cycle) receive electrons from NADH and FADH2, respectively. Electrons … Together, our studies highlight the key role of mitochondria in AD pathogenesis, and the close interrelationship of this organelle and the two main pathological hallmarks of this disease. Our data complement those obtained in another triple transgenic mouse model, 3xTg-AD (P301Ltau/APPSw/PS1 M146L) [70].

Mitochondrial dysfunction was evidenced by age-related decreased activity of regulatory enzymes of the oxidative phosphorylation system, and of PDH and COX in 3xTg-AD mice aged from 3 to 12 months [71]. These mice also exhibited increased oxidative stress and lipid peroxidation. Most of the effects on mitochondria were seen at the age of 9 months, whereas mitochondrial respiration was significantly decreased at 12 months of age. Importantly, mitochondrial bioenergetics deficits were found to precede the development of AD pathology in the 3xTg-AD mice. More recently, Hyun and colleagues [72] demonstrated that the plasma membrane redox system (PMRS) is impaired in the 3xTg-AD mice and that the activities of PMRS enzymes may protect neurons against A?? toxicity, suggesting enhancement of PMRS function as a novel approach for protecting neurons against oxidative Dacomitinib damage in AD and related disorders.

Collectively, these recent data consolidate the idea that a synergistic effect of tau and A?? augments the pathological deterioration of mitochondria at an early stage namely of AD. Conclusion We discuss here the critical role of mitochondria and the close interrelationship of this organelle with the two main pathological features in the pathogenic process underlying AD.