Amyloid-β and tau synergistically impair the oxidative phosphorylation system in triple transgenic Alzheimer's disease mice

Abstract

Alzheimer's disease (AD) is characterized by amyloid-beta (A␤)-containing plaques, neurofibrillary tangles, and neuron and synapse loss. Tangle formation has been reproduced in P301L tau transgenic pR5 mice, whereas APP sw PS2 N141I double-transgenic APP152 mice develop A␤ plaques. Cross-breeding generates triple transgenic ( triple AD) mice that combine both pathologies in one model. To determine functional consequences of the combined A␤ and tau pathologies, we performed a proteomic analysis followed by functional validation. Specifically, we obtained vesicular preparations from triple AD mice, the parental strains, and nontransgenic mice, followed by the quantitative mass-tag labeling proteomic technique iTRAQ and mass spectrometry. Within 1,275 quantified proteins, 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). Notably, deregulation of complex I was tau dependent, whereas deregulation of complex IV was A␤ dependent, both at the protein and activity levels. Synergistic effects of A␤ and tau were evident in 8-month-old triple AD mice as only they showed a reduction of the mitochondrial membrane potential at this early age. At the age of 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 A␤ and tau in perishing mitochondria. Our study establishes a molecular link between A␤ and tau protein in AD pathology in vivo, illustrating the potential of quantitative proteomics.amyloid-beta peptide ͉ electron transport chain ͉ energy metabolism ͉ mitochondrial complexes ͉ tau protein A lzheimer's disease (AD) is a devastating neurodegenerative disorder affecting Ͼ15 million people worldwide (1). The key histopathological features are amyloid-beta (A␤)-containing plaques and microtubule-associated protein tau-containing neurofibrillary tangles (NFTs), along with neuronal and synapse loss in selected brain areas (2, 3). In determining the role of distinct proteins in these processes, traditionally, candidate-driven approaches have been pursued, linking neuronal dysfunction to the distribution of known proteins in healthy compared with degenerating neurons, or in transgenic compared with control brain. In comparison, proteomics offers a powerful nonbiased approach as shown by us previously (4, 5).APP152 (APP/PS2) double-transgenic mice model the A␤ plaque pathology of AD (6); they coexpress the N141I mutant form of PS2 together with the APP sw mutant found in familial cases of AD. The mice display age-related cognitive deficits associated with discrete brain A␤ deposition and inflammation (6). pR5 mice model the tangle pathology of AD (7-9). They express P301L mutant tau found in familial cases of frontotemporal dementia (FTD), a dementia related to AD. The pR5 mice show a hippocampus-and amygdala-dependent behavioral impairment related to AD (10). Crossing of ...

Beta‐amyloid 1‐42 monomers, but not oligomers, produce PHF ‐like conformation of Tau protein

“…We used a mouse model that expresses wild‐type human Tau and does not spontaneously produce Tau aggregates. In previous reports, the capability of Aβ1‐42 to induce Tau aggregation was studied in mice expressing mutant human Tau, models of tauopathies (Lewis et al ., 2001; Oddo et al ., 2006; Rhein et al ., 2009; Nisbet et al ., 2015). …”

Mitochondrial respiratory chain dysfunction: Implications in neurodegeneration

“…For instance, over-expression of truncated tau plus Aβ treatment increased ROS production in cultured neurons (Quintanilla et al, 2012). In triple transgenic AD mice expressing tau and APP, the decreased respiratory rates and mitochondrial membrane potential in aged mice were enhanced in comparison with either APP or tau transgenic animals (Rhein et al, 2009). Nevertheless, a hierarchical relationship between both proteins has also been proposed, where tau would mediate Aβ toxicity (for a review see Ittner and Gotz, 2011).…”

“…To further complicate the view of mitochondrial dysfunction in AD, the microtubule associated protein tau, which in its phosphorylated state forms the neurofibrillary tangles detected in AD brains, can in turn induce mitochondrial alterations such as decreased expression of complex I and complex V subunits, subsequent decreases in these complexes activities, lower mitochondrial membrane potential, altered calcium buffering, increased ROS production and up-regulation of cellular antioxidants (David et al, 2005;Quintanilla et al, 2009;Rhein et al 2009;Quintanilla et al, 2012). Moreover, tau and Aβ can interact synergistically to impair mitochondrial function.…”

Tau-induced neurodegeneration: mechanisms and targets

“…In 2009, a transgenic mouse strain that mimics both Aβ plaque formation and tau tangles was analyzed and it was found that both the plaques and the tangles affected the OXPHOS of the mitochondria [105] . In a more recent work, it has been shown that reduction of the expression of soluble tau is important for the proper distribution of mitochondria in the neurons of rTg4510 mice [104] .…”

“…The phosphorylation state of tau has been implicated in the degeneration of neurons [101] and linked to mitochondrial dysfunction [102] . Tau has also been shown to be ubiquitinated and to be involved in the cellular distribution of mitochondria in mouse neurons [103,104] .In 2009, a transgenic mouse strain that mimics both Aβ plaque formation and tau tangles was analyzed and it was found that both the plaques and the tangles affected the OXPHOS of the mitochondria [105] . In a more recent work, it has been shown that reduction of the expression of soluble tau is important for the proper distribution of mitochondria in the neurons of rTg4510 mice [104] .…”