Convergence of amyloid-beta and tau pathologies on mitochondria in vivo

Abstract

The histopathological characteristics of Alzheimer's disease (AD) are amyloid-beta (Abeta) 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 pathologic features of the disease in brain. Using comparative, quantitative proteomics (iTRAQ) and mass spectroscopy, 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 Abeta dependent, both at the protein and activity levels. The (triple)AD mice showed synergistic effects of Abeta 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, again emphasizing synergistic, age-associated effects of Abeta and tau in impairing mitochondria. This review highlights the convergence of Abeta and tau on mitochondria and establishes a molecular link in AD pathology in vivo.

Fig. 1

The vicious cycle of bioenergetic defects in AD. Tau and Aβ, the two major histopathological hallmarks of AD, act synergistically on mitochondria inducing amplified oxidative phosphorylation system (OXPHOS) deficiencies thereby triggering a vicious cycle. Notably, deregulation of mitochondrial complex IV was shown to be Aβ dependent, while deregulation of complex I was tau dependent, both at the protein and activity levels. The strong decrease of the mitochondrial respiratory capacity and the drop of ATP production associated with oxidative stress may finally lead to the synaptic loss and neuronal death that characterizes AD