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Elevated levels of pro-apoptotic p53 and its oxidative modification by the lipid peroxidation product, HNE, in brain from subjects with amnestic mild cognitive impairment and Alzheimer's disease.

Cenini G, Sultana R, Memo M, Butterfield DA - J. Cell. Mol. Med. (2008)

Bottom Line: The tumor suppressor and transcription factor p53 plays a pivotal function in neuronal apoptosis triggered by oxidative stress.Apoptosis contributes to neuronal death in many neurological disorders, including AD.In addition, HNE may be a novel non-protein mediator of oxidative stress-induced neuronal apoptosis.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, Center of Membrane Sciences, and Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY 40506-0055, USA.

ABSTRACT
Oxidative stress has been implicated in the pathogenesis of Alzheimer's disease (AD). Both AD and arguably its earlier form, mild cognitive impairment (MCI), have elevated membrane oxidative damage in brain. The tumor suppressor and transcription factor p53 plays a pivotal function in neuronal apoptosis triggered by oxidative stress. Apoptosis contributes to neuronal death in many neurological disorders, including AD. In this study, we investigated p53 expression in a specific region of the cerebral cortex, namely the inferior parietal lobule (IPL), in MCI and AD brain, to test the hypothesis that alterations of this pro-apoptotic protein may be involved in neuronal death in the progression of AD. By immunoprecipitation assay, we also investigated whether 4-hydroxy-2-transnonenal (HNE), an aldehydic product of lipid peroxidation, was bound in excess to p53 in IPL from subjects with MCI and AD compared to control. Overall, the data provide evidence that p53 is involved in the neuronal death in both MCI and AD, suggesting that the observed alterations are early events in the progression of AD. In addition, HNE may be a novel non-protein mediator of oxidative stress-induced neuronal apoptosis.

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(A) and (B) represent blots of p53-HNE adduction studied from MCI, AD and control, respectively.(C) and (D) represent densitometric analysis of (A) and (B), respectively. Equal amount of protein (150 mg/lane) were immunoprecipitated by anti-p53 antibody, and immunoprecipitates were analyzed for HNE immunoreactivity by Western blotting.(A) is a representative blot of data obtained from seven control and MCI samples, and (B) is representative blot of data obtained from five control and AD samples, respectively. The control value was set to 100%, to which experimental values were compared. AD, #P < 0.004.
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fig02: (A) and (B) represent blots of p53-HNE adduction studied from MCI, AD and control, respectively.(C) and (D) represent densitometric analysis of (A) and (B), respectively. Equal amount of protein (150 mg/lane) were immunoprecipitated by anti-p53 antibody, and immunoprecipitates were analyzed for HNE immunoreactivity by Western blotting.(A) is a representative blot of data obtained from seven control and MCI samples, and (B) is representative blot of data obtained from five control and AD samples, respectively. The control value was set to 100%, to which experimental values were compared. AD, #P < 0.004.

Mentions: To determine if HNE also binds to p53 protein to potentially influence its pro-apoptotic activity, an immunoprecipitation experiment was performed using an antibody that binds to and precipitates p53. This complex was then probed with an antibody against HNE-bound proteins by Western blotting analysis. The results showed a significant difference in AD IPL compared to the controls (Fig. 2B; #P < 0.004), but no significant difference in HNE bound to p53 in MCI samples (Fig. 2A), though the mean level was elevated.


Elevated levels of pro-apoptotic p53 and its oxidative modification by the lipid peroxidation product, HNE, in brain from subjects with amnestic mild cognitive impairment and Alzheimer's disease.

Cenini G, Sultana R, Memo M, Butterfield DA - J. Cell. Mol. Med. (2008)

(A) and (B) represent blots of p53-HNE adduction studied from MCI, AD and control, respectively.(C) and (D) represent densitometric analysis of (A) and (B), respectively. Equal amount of protein (150 mg/lane) were immunoprecipitated by anti-p53 antibody, and immunoprecipitates were analyzed for HNE immunoreactivity by Western blotting.(A) is a representative blot of data obtained from seven control and MCI samples, and (B) is representative blot of data obtained from five control and AD samples, respectively. The control value was set to 100%, to which experimental values were compared. AD, #P < 0.004.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4401131&req=5

fig02: (A) and (B) represent blots of p53-HNE adduction studied from MCI, AD and control, respectively.(C) and (D) represent densitometric analysis of (A) and (B), respectively. Equal amount of protein (150 mg/lane) were immunoprecipitated by anti-p53 antibody, and immunoprecipitates were analyzed for HNE immunoreactivity by Western blotting.(A) is a representative blot of data obtained from seven control and MCI samples, and (B) is representative blot of data obtained from five control and AD samples, respectively. The control value was set to 100%, to which experimental values were compared. AD, #P < 0.004.
Mentions: To determine if HNE also binds to p53 protein to potentially influence its pro-apoptotic activity, an immunoprecipitation experiment was performed using an antibody that binds to and precipitates p53. This complex was then probed with an antibody against HNE-bound proteins by Western blotting analysis. The results showed a significant difference in AD IPL compared to the controls (Fig. 2B; #P < 0.004), but no significant difference in HNE bound to p53 in MCI samples (Fig. 2A), though the mean level was elevated.

Bottom Line: The tumor suppressor and transcription factor p53 plays a pivotal function in neuronal apoptosis triggered by oxidative stress.Apoptosis contributes to neuronal death in many neurological disorders, including AD.In addition, HNE may be a novel non-protein mediator of oxidative stress-induced neuronal apoptosis.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, Center of Membrane Sciences, and Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY 40506-0055, USA.

ABSTRACT
Oxidative stress has been implicated in the pathogenesis of Alzheimer's disease (AD). Both AD and arguably its earlier form, mild cognitive impairment (MCI), have elevated membrane oxidative damage in brain. The tumor suppressor and transcription factor p53 plays a pivotal function in neuronal apoptosis triggered by oxidative stress. Apoptosis contributes to neuronal death in many neurological disorders, including AD. In this study, we investigated p53 expression in a specific region of the cerebral cortex, namely the inferior parietal lobule (IPL), in MCI and AD brain, to test the hypothesis that alterations of this pro-apoptotic protein may be involved in neuronal death in the progression of AD. By immunoprecipitation assay, we also investigated whether 4-hydroxy-2-transnonenal (HNE), an aldehydic product of lipid peroxidation, was bound in excess to p53 in IPL from subjects with MCI and AD compared to control. Overall, the data provide evidence that p53 is involved in the neuronal death in both MCI and AD, suggesting that the observed alterations are early events in the progression of AD. In addition, HNE may be a novel non-protein mediator of oxidative stress-induced neuronal apoptosis.

Show MeSH
Related in: MedlinePlus