Convergence of amyloid-beta and tau pathologies on mitochondria in vivo.
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.
Eckert
Anne
A
Neurobiology Laboratory for Brain Aging and Mental Health, Psychiatric University Clinics, University of Basel, 4025, Basel, Switzerland. Anne.Eckert@upkbs.ch
Schulz
Kathrin L
KL
Rhein
Virginie
V
Götz
Jürgen
J
D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology*; D053763:Presenilins / Q000235:genetics / Q000378:metabolism; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D053763:Presenilins; D016875:tau Proteins