Oxidative Stress Increases Expression and Activity of BACE in NT2 Neurons

Tamagno, Elena; Bardini, Paola; Obbili, Alessandra; Vitali, Antonella; Borghi, Roberta; Zaccheo, D; Pronzato, Maria Adelaide; Danni, Oliviero; Smith, Mark A.; Perry, George; Tabaton, Massimo

doi:10.1006/nbdi.2002.0515

Cited by 350 publications

(297 citation statements)

References 36 publications

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“…This finding supports a functional role for oxidative stress in regulating the amyloidogenic response to brain trauma in vivo, and it is consistent with some in vitro data showing that oxidative stress can positively modulate APP metabolism and increase in Ab formation (Misonou et al 2000). Thus, previous studies have shown that oxidants can indeed increased BACE activity and amyloid formation in neuronal cell lines (Tamagno et al 2002).…”

Section: Discussionsupporting

confidence: 90%

Vitamin E reduces amyloidosis and improves cognitive function in Tg2576 mice following repetitive concussive brain injury

Conte

Uryu

Fujimoto

et al. 2004

Journal of Neurochemistry

143

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Traumatic brain injury is a well-recognized environmental risk factor for developing Alzheimer's disease. Repetitive concussive brain injury (RCBI) exacerbates brain lipid peroxidation, accelerates amyloid (Ab) formation and deposition, as well as cognitive impairments in Tg2576 mice. This study evaluated the effects of vitamin E on these four parameters in Tg2576 mice following RCBI. Eleven-month-old mice were randomized to receive either regular chow or chow-supplemented with vitamin E for 4 weeks, and subjected to RCBI (two injuries, 24 h apart) using a modified controlled cortical impact model of closed head injury. The same dietary regimens were maintained up to 8 weeks post-injury, when the animals were killed for biochemical and immunohistochemical analyses after behavioral evaluation. Vitamin E-treated animals showed a significant increase in brain vitamin E levels and a significant decrease in brain lipid peroxidation levels. After RBCI, compared with the group on regular chow, animals receiving vitamin E did not show the increase in Ab peptides, and had a significant attenuation of learning deficits. This study suggests that the exacerbation of brain oxidative stress following RCBI plays a mechanistic role in accelerating Ab accumulation and behavioral impairments in the Tg2576 mice.

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Section: Discussionsupporting

confidence: 90%

Vitamin E reduces amyloidosis and improves cognitive function in Tg2576 mice following repetitive concussive brain injury

Conte

Uryu

Fujimoto

et al. 2004

Journal of Neurochemistry

143

View full text Add to dashboard Cite

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“…These studies consistently demonstrated a strong correlation between oxidative stress and accumulation of Aβ with the possible involvement of an APP-processing enzyme, β-secretase [53][54][55][56][57]. A recent report using heterozygous Mn-SOD knockout mice also showed that oxidative stress modulates hyperphosphorylation of tau, which leads to the formation of neurofibrillary tangles [58].…”

Section: Contribution Of Complex IV Defects To Oxidative Stress and Nmentioning

confidence: 84%

The mitochondrial impairment, oxidative stress and neurodegeneration connection: reality or just an attractive hypothesis?

Fukui

Moraes

2008

Trends in Neurosciences

221

146

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Aging is the most important risk factor for common neurodegenerative disorders such as Parkinson's and Alzheimer's diseases. Aging in the central nervous system has been associated with elevated mutation load in mitochondrial DNA, defects in mitochondrial respiration and increased oxidative damage. These observations support a 'vicious cycle' theory which states that there is a feedback mechanism connecting these events in aging and age-associated neurodegeneration. Despite being an extremely attractive hypothesis, the bulk of the evidence supporting the mitochondrial vicious cycle model comes from pharmacological experiments in which the modes of mitochondrial enzyme inhibition are far from those observed in real life. Furthermore, recent in vivo evidence does not support this model. In this review, we focus on the relationship among the components of the putative vicious cycle, with particular emphasis on the role of mitochondrial defects on oxidative stress. Mitochondrial respiratory chain and reactive oxygen species productionMitochondria, being the key players in ATP production and diverse cell signaling events, are essential organelles for the survival of eukaryotic cells. Unlike all other organelles in animals, the mitochondria have their own genome (mitochondrial DNA; mtDNA) that encodes components of the oxidative phosphorylation (OXPHOS) system. The mitochondrial OXPHOS machinery is composed of five multisubunit complexes (complex I-V). From Krebs cycle intermediates (NADH and FADH 2 ), electrons feed into complex I or II, and are transferred to complex III, then to complex IV, and finally to O 2 . The redox energy released during the electron transfer process in complexes I, III and IV is utilized to actively pump out H + from the mitochondrial matrix to the intermembrane space, generating the electrochemical gradient of H + across the inner membrane which is ultimately utilized by complex V to produce ATP [1].This elegant system for energy production, however, is not perfect. A small portion (up to 2%) of electrons passing through the electron transport chain, mostly at complex I and complex III, react with molecular oxygen and yield superoxide anion, which can be converted into other reactive oxygen species (ROS) such as hydrogen peroxide and the highly reactive hydroxyl radical through enzymatic and nonenzymatic reactions [2]. Cells are endowed with robust endogenous antioxidant systems to counteract excessive ROS. It is believed that ROS, in particular hydrogen peroxide, have physiological roles as signaling molecules [3,4]. However,

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“…Because the inflammatory response to A␤ peptide partly involves the CD14 immune response (Fassbender et al, 2004;Milatovic et al, 2004), and A␤ peptide can induce microglial production of superoxide (Bianca et al, 1999), one hypothesis that emerges is that EP2-mediated oxidative stress indirectly promotes increased A␤ peptide levels via increased BACE1 processing. Recent investigations have linked increases in oxidative stress to increases in BACE1 activity and production of ␤-CTF (Tamagno et al, 2002;Apelt et al, 2004). Increases in BACE1 processing have also been demonstrated in aging and AD, in which inflammation and oxidative stress are prominent features (Fukumoto et al, 2002(Fukumoto et al, , 2004Yang et al, 2003;Apelt et al, 2004;Holsinger et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

“…Association of oxidative inflammatory response and increased A␤ peptide levels in APPSwe-PS1⌬E9 in EP2؉/؉ background Recent studies have demonstrated that BACE1 processing of APP is increased in aging and AD (Fukumoto et al, 2002(Fukumoto et al, , 2004Holsinger et al, 2002;Yang et al, 2003;Li et al, 2004), and this may relate to effects of increased oxidative stress on BACE1 activity (Tamagno et al, 2002;Apelt et al, 2004). EP2 receptor signaling leads to a marked inflammatory oxidative response in the LPS model of innate immunity (T. J.…”

Section: Deletion Of the Ep2 Receptor In Appswe-ps1⌬e9 Mice Reduces Lmentioning

confidence: 99%

Deletion of the Prostaglandin E₂EP2 Receptor Reduces Oxidative Damage and Amyloid Burden in a Model of Alzheimer's Disease

Liang¹,

Wang²,

Hand³

et al. 2005

J. Neurosci.

219

202

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Epidemiological studies demonstrate that chronic use of nonsteroidal anti-inflammatory drugs (NSAIDs) in normal aging populations reduces the risk of developing Alzheimer's disease (AD). NSAIDs inhibit the enzymatic activity of cyclooxygenase-1 (COX-1) and inducible COX-2, which catalyze the first committed step in the synthesis of prostaglandins. These studies implicate COX-mediated inflammation as an early and potentially reversible preclinical event; however, the mechanism by which COX activity promotes development of AD has not been determined. Recent studies implicate the prostaglandin E 2 (PGE 2 ) E prostanoid subtype 2 (EP2) receptor in the development of the innate immune response in brain. Here, we report that deletion of the PGE 2 EP2 receptor in the APPSwe-PS1⌬E9 model of familial AD results in marked reductions in lipid peroxidation in aging mice. This reduction in oxidative stress is associated with significant decreases in levels of amyloid-␤ (A␤) 40 and 42 peptides and amyloid deposition. Aged APPSwe-PS1⌬E9 mice lacking the EP2 receptor harbor lower levels of ␤ C-terminal fragments, the product of ␤-site APP cleaving enzyme (BACE1) processing of amyloid precursor protein. Increases in BACE1 processing have been demonstrated in models of aging and AD and after oxidative stress. Our results indicate that PGE 2 signaling via the EP2 receptor promotes age-dependent oxidative damage and increased A␤ peptide burden in this model of AD, possibly via effects on BACE1 activity. Our findings identify EP2 receptor signaling as a novel proinflammatory and proamyloidogenic pathway in this model of AD, and suggest a rationale for development of therapeutics targeting the EP2 receptor in neuroinflammatory diseases such as AD.

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Oxidative Stress Increases Expression and Activity of BACE in NT2 Neurons

Cited by 350 publications

References 36 publications

Vitamin E reduces amyloidosis and improves cognitive function in Tg2576 mice following repetitive concussive brain injury

Vitamin E reduces amyloidosis and improves cognitive function in Tg2576 mice following repetitive concussive brain injury

The mitochondrial impairment, oxidative stress and neurodegeneration connection: reality or just an attractive hypothesis?

Deletion of the Prostaglandin E₂EP2 Receptor Reduces Oxidative Damage and Amyloid Burden in a Model of Alzheimer's Disease

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Oxidative Stress Increases Expression and Activity of BACE in NT2 Neurons

Cited by 350 publications

References 36 publications

Vitamin E reduces amyloidosis and improves cognitive function in Tg2576 mice following repetitive concussive brain injury

Vitamin E reduces amyloidosis and improves cognitive function in Tg2576 mice following repetitive concussive brain injury

The mitochondrial impairment, oxidative stress and neurodegeneration connection: reality or just an attractive hypothesis?

Deletion of the Prostaglandin E2EP2 Receptor Reduces Oxidative Damage and Amyloid Burden in a Model of Alzheimer's Disease

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Deletion of the Prostaglandin E₂EP2 Receptor Reduces Oxidative Damage and Amyloid Burden in a Model of Alzheimer's Disease