Elevated protein-bound levels of the lipid peroxidation product, 4-hydroxy-2-nonenal, in brain from persons with mild cognitive impairment

Butterfield, D. Allan; Reed, Tanea T.; Perluigi, Marzia; Marco, C. De; Coccia, Raffaella; Cini, Chiara; Sultana, Rukhsana

doi:10.1016/j.neulet.2005.12.017

Cited by 223 publications

(165 citation statements)

References 29 publications

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“…Protein carbonyls, 3-NT and HNE levels are elevated in AD and MCI brains [3,4,[7][8][9][10][11][12]21,22]. HNE is a highly reactive product of arachidonic acid metabolism that is believed to interfere with normal cellular functions [3].…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies indicate that protein oxidation and lipid peroxidation in brain from mild cognitive impairment subjects [21,22], suggesting oxidative stress is an early event in the pathogenesis of AD. ROS generation from mitochondria and its impact on neuronal systems hence becomes important in understanding oxidative stress and oxidative stress-related disorders, including AD.…”

Section: Introductionmentioning

confidence: 99%

“…It is now well known that ROS such as superoxide anion (O 2 -), hydroxyl radical (OH), hydrogen peroxide (H 2 O 2 ), and peroxynitrite (ONOO -) contribute to neurodegeneration [21,[24][25][26][27][28]. Mitochondrial membrane potential depolarization induces cytochrome-c release into the cytoplasm and elevates the activity of caspase-3, suggesting a role for mtDNA-derived mitochondrial dysfunction in AD degeneration [5].…”

Section: Introductionmentioning

confidence: 99%

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In vivo administration of D609 leads to protection of subsequently isolated gerbil brain mitochondria subjected to in vitro oxidative stress induced by amyloid beta-peptide and other oxidative stressors: Relevance to Alzheimer’s disease and other oxidative stress-related neurodegenerative disorders

Ansari

Joshi

Huang

et al. 2006

Free Radical Biology and Medicine

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Tricyclodecan-9-yl-xanthogenate (D609) has in vivo and in vitro antioxidant properties. D609 mimics glutathione (GSH), has a free thiol group, which upon oxidation forms a disulfide. The resulting dixanthate is a substrate for glutathione reductase, regenerating D609. Recent studies have also shown that D609 protects brain in vivo and neuronal cultures in vitro against the potential Alzheimer's disease (AD) causative factor, Aβ (1-42)-induced oxidative stress and cytotoxicity. Mitochondria are important organelles with both pro-and anti-apoptotic factor proteins. The present study was undertaken to test the hypothesis that i.p. injection of D609 would provide neuroprotection against free radical-induced, mitochondria-mediated apoptosis in vitro. Brain mitochondria were isolated from gerbils 1 h post injection intraperitonially (i.p.) with D609 and subsequently treated in vitro with the oxidants Fe 2+ /H 2 O 2 (hydroxyl free radicals), 2,2-azobis-(2-amidinopropane) dihydrochloride (AAPH, alkoxyl and peroxyl free radicals) and AD-relevant amyloid β-peptide 1-42 [Aβ (1-42)]. Brain mitochondria isolated from the gerbils previously injected i.p. with D609 and subjected to these oxidative stress inducers, in vitro, showed significant reduction in levels of protein carbonyls, protein-bound hydroxynonenal (HNE) [a lipid peroxidation product], 3-nitrotyrosine (3-NT), and cytochrome-c release compared to oxidant-treated brain mitochondria isolated from salineinjected gerbils. D609 treatment significantly maintains the GSH/GSSG ratio in oxidant-treated mitochondria. Increased activity of glutathione-S-transferase (GST), glutathione peroxidase (GPx) and glutathione reductase (GR) in brain isolated from D609-injected gerbils is consistent with the notion that D609 acts like GSH. These anti-apoptotic findings are discussed with reference to the potential use of this brain-accessible glutathione mimetic in the treatment of oxidative stress-related neurodegenerative disorders, including AD.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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In vivo administration of D609 leads to protection of subsequently isolated gerbil brain mitochondria subjected to in vitro oxidative stress induced by amyloid beta-peptide and other oxidative stressors: Relevance to Alzheimer’s disease and other oxidative stress-related neurodegenerative disorders

Ansari

Joshi

Huang

et al. 2006

Free Radical Biology and Medicine

Self Cite

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“…However, one recent study ascertained that the effector caspase-6 was intimately linked to pathological hallmarks of AD in the hippocampus of persons with all stages of AD, including MCI and NCI (severely aged cognitively normal) (Albrecht et al, 2007). The present study investigated the hypothesis that PtdSer asymmetry is significantly altered in the inferior parietal lobule (IPL) of subjects with MCI and AD, which suggests that increased production of lipid peroxidation products (Butterfield et al, 2006a) and levels of apoptotic proteins may work together to affect PtdSer asymmetry even in MCI, arguably the earliest form of AD.…”

Section: Introductionmentioning

confidence: 93%

“…Amnestic mild cognitive impairment (MCI) is considered a transition point between normal cognitive aging and dementia or probable AD (Petersen et al, 1999;Winblad et al, 2004). Brain samples from MCI subjects are reported to have increased oxidative stress (Butterfield et al, 2006b;Keller et al, 2005;Markesbery et al, 2005;Petersen et al, 1999) that can be associated with increased levels of reactive alkenals (Butterfield et al, 2006a). Unfortunately, not much is known about apoptotic processes with respect to MCI to date.…”

Section: Introductionmentioning

confidence: 99%

Loss of phospholipid asymmetry and elevated brain apoptotic protein levels in subjects with amnestic mild cognitive impairment and Alzheimer disease

Lange

Cenini

Piroddi

et al. 2008

Neurobiology of Disease

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Oxidative stress, a hallmark of Alzheimer disease (AD), has been shown to induce lipid peroxidation and apoptosis disrupting cellular homeostasis. Normally, the aminophospholipid phosphatidylserine (PtdSer) is asymmetrically distributed on the cytosolic leaflet of the lipid bilayer. Under oxidative stress conditions, asymmetry is altered, characterized by the appearance of PtdSer on the outer leaflet, to initiate the first stages of an apoptotic process. PtdSer asymmetry is actively maintained by the ATP-dependent translocase flippase, whose function is inhibited if covalently bound by lipid peroxidation products, 4-hydroxynonenal (HNE) and acrolein, within the membrane bilayer in which they are produced. Additionally, pro-apoptotic proteins Bax and caspase-3 have been implemented in the oxidative modification of PtdSer resulting in subsequent asymmetric collapse, while antiapoptotic protein Bcl-2 has been found to prevent this process.The current investigation focused on detection of PtdSer on the outer leaflet of the bilayer in synaptosomes from brain of subjects with AD and amnestic mild cognitive impairment (MCI), as well as expression levels of apoptosis-related proteins Bcl-2, Bax, and caspase-3. Fluorescence and Western blot analysis suggest PtdSer exposure on the outer leaflet is significantly increased in brain from subjects with MCI and AD contributing to early apoptotic elevation of pro-and anti-apoptotic proteins and finally neuronal loss. MCI is considered a possible transition point between normal cognitive aging and probable AD. Brain from subjects with MCI is reported to have increased levels of tissue oxidation; therefore, the results of this study could mark the progression of patients with MCI into AD. This study contributes to a model of apoptosis-specific oxidation of phospholipids consistent with the notion that PtdSer exposure is required for apoptotic-cell death.

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Role of Oxidatively Stressed Lipids in Amyloid Formation and Toxicity

Axelsen

Komatsu

2010

Protein Misfolding Diseases

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Elevated protein-bound levels of the lipid peroxidation product, 4-hydroxy-2-nonenal, in brain from persons with mild cognitive impairment

Cited by 223 publications

References 29 publications

Loss of phospholipid asymmetry and elevated brain apoptotic protein levels in subjects with amnestic mild cognitive impairment and Alzheimer disease

Role of Oxidatively Stressed Lipids in Amyloid Formation and Toxicity

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