Oxidative Stress Signaling in Alzheimers Disease

Su, Bo; Wang, Xinglong; Nunomura, Akihiko; Moreira, Paula I.; Lee, H. Gon; Perry, George; Smith, Mark A.; Zhu, Xiongwei

doi:10.2174/156720508786898451

Cited by 261 publications

(216 citation statements)

References 131 publications

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“…Our findings are in line with recent studies associating A␤ and tau with oxidative stress (17,18,28). Moreover, APP transport was shown to be impaired by elevated tau, suggesting a possible link of the 2 proteins (28,29).…”

Section: Discussionsupporting

confidence: 93%

“…Energy deficiency and mitochondrial dysfunction have been recognized as a prominent, early event in AD, but the mechanisms leading to mitochondrial failure are not well understood (15,(17)(18)(19)(20)(21)(22)(23)(24). Recently, we had shown in vivo that P301L mutant tau was capable of inducing mitochondrial dysfunction and increasing levels of ROS in pR5 mice (4).…”

Section: Discussionmentioning

confidence: 99%

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

Rhein

Song

Wiesner

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

593

486

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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 ...

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

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

Rhein

Song

Wiesner

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

593

486

View full text Add to dashboard Cite

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“…AD is considered as a neurodegenerative disease, however, and multiple pieces of evidence show that oxidative stress may also have a pathogenic role in AD. 51 These results suggest that LPL might have a role in the antioxidation stress of brain through lipids scavenging and recycling, bonding function and other unrecognized mechanisms, and indicate that LPL may be a protective factor of AD. Therefore, dysfunction of antioxidation stress induced by LPL aberration, in the brain, might be a risk factor of AD.…”

Section: Lpl and Ehmentioning

confidence: 75%

The common biological basis for common complex diseases: evidence from lipoprotein lipase gene

et al. 2009

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The lipoprotein lipase (LPL) gene encodes a rate-limiting enzyme protein that has a key role in the hydrolysis of triglycerides. Hypertriglyceridemia, one widely prevalent syndrome of LPL deficiency and dysfunction, may be a risk factor in the development of dyslipidemia, type II diabetes (T2D), essential hypertension (EH), coronary heart disease (CHD) and Alzheimer's disease (AD). Findings from earlier studies indicate that LPL may have a role in the pathology of these diseases and therefore is a common or shared biological basis for these common complex diseases. To examine this hypothesis, we reviewed articles on the molecular structure, expression and function of the LPL gene, and its potential role in the etiology of diseases. Evidence from these studies indicate that LPL dysfunction is involved in dyslipidemia, T2D, EH, CHD and AD; and support the hypothesis that there is a common or shared biological basis for these common complex diseases.

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“…The reactive oxygen species (ROS) 2 produced play important roles in cell signaling and homeostasis (1), but they also elicit cellular toxicity that causes disease (2)(3)(4). Phagocytes such as macrophages and neutrophils utilize ROS for the digestion of invading bacteria (5,6), where the voltage-gated H ϩ channel (called the Hv channel) optimizes the activity of NADPH oxidase that produces ROS (see Fig.…”

mentioning

confidence: 99%

Structural Characteristics of the Redox-sensing Coiled Coil in the Voltage-gated H+ Channel

Fujiwara¹,

Takeshita

Nakagawa

et al. 2013

Journal of Biological Chemistry

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Background: A pair of Cys residues is present in the coiled-coil assembly domain in the Hv channel dimer. Results: An intersubunit disulfide bond forms in a redox-dependent manner and stabilizes the dimeric assembly. Conclusion:The Hv channel has a redox sensor in the cytoplasmic region. Significance: Hv channels expressed in phagocytes may sense the redox condition in production of reactive oxygen species for repelling bacteria.

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Oxidative Stress Signaling in Alzheimers Disease

Cited by 261 publications

References 131 publications

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

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

The common biological basis for common complex diseases: evidence from lipoprotein lipase gene

Structural Characteristics of the Redox-sensing Coiled Coil in the Voltage-gated H+ Channel

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