Enhanced oxidative stress is an early event during development of Alzheimer-like pathologies in presenilin conditional knock-out mice

Gu, Feng; Zhu, Manjie; Shi, Jianting; Hu, Yinghe; Zhao, Zheng

doi:10.1016/j.neulet.2008.05.050

Cited by 75 publications

(59 citation statements)

References 34 publications

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“…3). consistent with the previous study [22] . However, using isoprostanes as a marker, Zhu et al found that lipid peroxidation was enhanced in an age dependent manner [23] , which suggested that there were different lipid peroxidative products at various age points induced by PS1/PS2 double knockout, and isoprostanes could be a more sensitive indicator of lipid peroxidation.…”

Section: Protein Oxidation Profile In Dko Micesupporting

confidence: 94%

“…In general, our results and previous findings [22,23] suggest that activities of antioxidant enzymes, such as SOD and GSH-PX, had no significant alterations in dKO cortex, which indicated the imbalance between the unchanged defense system and the increased oxidative system, finally resulting in oxidative damage, especially DNA damage, in dKO mice brain. As mentioned above, our results confirmed that the protein level of Aβ 42 was significantly decreased.…”

Section: Discussionsupporting

confidence: 72%

“…What is the real correlation between oxidative stress and Alzheimer-like symptoms induced by PS1/PS2 double knockout? A group in our lab had found that oxidative stress enhancement appeared at early stages (≤ 7 months) and lipid peroxidation was enhanced in a genderand age-related manner in dKO mice [22,23] . The present study therefore aims to thoroughly investigate oxidative stress status in dKO mice not only at early stages but also at late stages, by examining the oxidative products in multi-levels-lipid, protein, DNA and antioxidase levels in brain.…”

Section: Introductionmentioning

confidence: 95%

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Oxidative damage increased in presenilin1/presenilin2 conditional double knockout mice

Zhang¹,

Chen²,

Xu³

et al. 2009

Neurosci. Bull.

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Objective This report aims to describe the oxidative damage profile in brain of presenilin1 and presenilin2 conditional double knockout mice (dKO) at both early and late age stages, and to discuss the correlation between oxidative stress and the Alzheimer-like phenotypes of dKO mice. Methods The protein level of Aβ 42 in dKO cortex and free 8-OHdG level in urine were measured by ELISA. Thiobarbituric acid method and spectrophotometric DNPH assay were used to determine the lipid peroxidation and protein oxidation in cortex, respectively. SOD and GSH-PX activities were assessed by SOD Assay Kit-WST and GSH-PX assay kit, separately. Results Significant decrease of Aβ 42 was verified in dKO cortex at 6 months as compared to control mice. Although lipid peroxidation (assessed by MDA) was increased only in dKO cortex at 3 months and protein oxidation (assessed by carbonyl groups) was basically unchanged in dKO cortex, ELISA analysis revealed that free 8-OHdG, which was an indicator of DNA lesion, was significantly decreased in urine of dKO mice from 3 months to 12 months. Activities of SOD and GSH-PX in dKO and control cortices showed no statistical difference except a significant increase of GSH-PX activity in dKO mice at 9 months. Conclusion Oxidative damage, especially DNA lesion, was correlated with the neurodegenerative symptoms that appeared in dKO mice without the deposition of Aβ 42 . Triggers of oxidative damage could be the inflammatory mediators released by activated microglia and astrocytes.

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Section: Protein Oxidation Profile In Dko Micesupporting

confidence: 94%

Section: Discussionsupporting

confidence: 72%

Section: Introductionmentioning

confidence: 95%

See 1 more Smart Citation

Oxidative damage increased in presenilin1/presenilin2 conditional double knockout mice

Zhang¹,

Chen²,

Xu³

et al. 2009

Neurosci. Bull.

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“…Glutathione is one of the major antioxidants in the human body, and oxidative stress has been implicated in a number of brain disorders, including Alzheimer's Disease and major depression. [13][14][15][16][17][18] Homocysteine, which is converted to methionine, is part of a reaction that requires methyltetrahydrofolate as a methyl group donor. States of folate deficiency have been shown to lower brain SAM levels and result in hypomethylation.…”

Section: Discussionmentioning

confidence: 99%

Proteomic-based genotyping in a mouse model of trait anxiety exposes disease-relevant pathways

et al. 2009

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In our biomarker identification efforts, we have reported earlier on a protein that differs in its electrophoretic mobility between mouse lines bred either for high or low trait anxiety. The altered electrophoretic behavior of enolase phosphatase (EP) is now identified to be caused by two single-nucleotide polymorphisms. In both cases, the genetic polymorphism introduces an amino acid change in the protein's sequence resulting in differential mobility on SDS gels. This was shown by recombinantly expressing the two EP isoforms. Functional studies indicate that the EP isoform from the high anxiety mouse line has a lower enzymatic activity than does its low anxiety mouse counterpart. EP is a member of the methionine salvage pathway that is responsible for the synthesis of S-adenosyl-L-methionine, a natural compound with potential antidepressant activities. In addition, it is linked to the polyamine pathway whose members have functions in anxiety/depression-related behaviors. In a freely-segregating F2 panel, both single-nucleotide polymorphisms were significantly associated with locomotion-independent trait anxiety, further supporting a functional role of EP for this phenotype. The study shows that proteomic analysis can reveal genotypic differences relevant for the phenotype. The identified protein alterations, in turn, can expose metabolic pathways pertinent to the behavioral phenotype.

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“…The ROS can be scavenged by endogenous antioxidants including superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px). Malondialdehyde (MDA) is a by-product of lipid peroxidation induced by free radicals and is widely used as a biomarker of oxidative stress (8). One approach against ROS in neurodegenerative disorders is to enhance oxidative defenses via antioxidants (7).…”

Section: Introductionmentioning

confidence: 99%

Ligustrazine Phosphate Ethosomes for Treatment of Alzheimer’s Disease, In Vitro and in Animal Model Studies

2012

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Abstract. In the present study, we have investigated transdermal administration of ligustrazine phosphate (LP), as an antioxidant, for the treatment of Alzheimer's disease (AD). The LP transdermal ethosomal system was designed and characterized. Franz-type diffusion cells and confocal laser scanning microscopy were used for the in vitro permeation studies. Furthermore, the effect of LP transdermal ethosomal system on AD was evaluated in the scopolamine-induced amnesia rats by evaluating the behavioral performance in the Morris water maze test. The activities of the antioxidant enzymes and the levels of the lipid peroxidation product malondialdehyde (MDA) in the brain of rats were also determined. The results showed that both the penetration ability and the drug deposition in skin of the LP ethosomal system were significantly higher than the aqueous one. The LP transdermal ethosomal system could recover the activities of the antioxidant enzymes and the levels of MDA in the brain of the amnesic rats to the similar status of the normal rats, which was also indirectly reflected by the improvement in the behavioral performance. In conclusion, LP might offer a potential alternative therapeutic drug in the fight against AD, and ethosomes could be vesicles of choice for transdermal delivery of LP.

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Enhanced oxidative stress is an early event during development of Alzheimer-like pathologies in presenilin conditional knock-out mice

Cited by 75 publications

References 34 publications

Oxidative damage increased in presenilin1/presenilin2 conditional double knockout mice

Oxidative damage increased in presenilin1/presenilin2 conditional double knockout mice

Proteomic-based genotyping in a mouse model of trait anxiety exposes disease-relevant pathways

Ligustrazine Phosphate Ethosomes for Treatment of Alzheimer’s Disease, In Vitro and in Animal Model Studies

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