Convergence of Amyloid-β and Tau Pathologies on Mitochondria In Vivo

Abstract

The histopathological characteristics of Alzheimer’s disease (AD) are amyloid-β (Aβ) 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)—tripleAD 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 Aβ dependent, both at the protein and activity levels. The tripleAD mice showed synergistic effects of Aβ 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 tripleAD mice, again emphasizing synergistic, age-associated effects of Aβ and tau in impairing mitochondria. This review highlights the convergence of Aβ and tau on mitochondria and establishes a molecular link in AD pathology in vivo.

Tau Accumulation Causes Mitochondrial Distribution Deficits in Neurons in a Mouse Model of Tauopathy and in Human Alzheimer's Disease Brain

“…The fact that alterations in mitochondrial distribution are evident at early stages, in the 5.5 month rTg4510, supports the notion that transport deficits and accompanying mitochondrial changes in distribution are early events in neurodegenerative cascades. 19,23,24,42,43 Several potential mechanisms for tau overexpression contributing to transport deficits have previously been explored. (1) Studies of tau over-expression in cells and in vitro assays have demonstrated negative consequences to anterograde cellular transport, by directly inhibiting progress of kinesin-1, by forming a "road block" on the microtubule where excessive tau is bound.…”

“…50,51 Furthermore, tau over-expression in vitro has been shown to result in increased mitochondrial fragmentation, alterations in mitochondrial membrane potential, impaired calcium buffering and oxidative stress responses, and diminished respiratory chain function. 19,43,52 For these reasons, we assessed mitochondrial volumes in the 8.5 month-old rTg4510 and nonTg mice to determine whether concomitant disequilibrium in fission and fusion dynamics is evident alongside mitochondrial distribution deficits. We did not find significant differences in mitochondrial size in the neuropil, which is consistent with a proteomic study of P301L mutant tau over-expressing mice.…”

“…Failure to properly distribute mitochondria throughout the cell leaves synapses deprived of their energy requirements, susceptible to reactive oxygen species, and with inefficient calcium handling and can result in synaptic dysfunction and subsequent dying back of the neuron. 15,19,20,53 When improperly distributed, mitochondria are thought to have impaired function 25,54 and this can lead to increased neuronal susceptibility to excitotoxicity or neurodegenerative stressors such as amyloid-␤. 2 Changes to mitochondrial distribution have been linked to failure to maintain mitochondrial membrane potential, resulting in release and activation of pro-apoptotic molecules such as caspase.…”

Targeting the Prodromal Stage of Alzheimer's Disease: Bioenergetic and Mitochondrial Opportunities

“…Dysfunctional mitochondria produce high levels of reactive oxygen species (ROS); these ROS can negatively affect specific mitochondrial components, including mitochondrial DNA (mtDNA), membrane lipids, and oxidative phosphorylation proteins [18,19]. For example dysregulation of complex I has been correlated with tau toxicity, and dysregulation of complex IV has been associated with increased Aβ load [20][21][22]. Additionally, specific proteins are affected by mitochondrial dysfunction in AD, including amyloid precursor protein, presenilin 1 and presenilin 2, which reside along the mitochondria-associated endoplasmic reticulum membranes [23].…”

Mitochondrial Dysfunction and Alzheimer’s Disease

“…In Europe, nine different mitochondrial haplogroups have been identified (H, I, J, K, T, U, V, W and X). This lead to a suggestion that inherited European mitochondrial haplogroups may be related to longevity, as well as AD risk in Caucasians [4, 11,12].…”