Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Down syndrome is caused by over-expression of genes located within a segment of chromosome 21, termed the Down locus. Down syndrome is associated with developmental abnormalities of the central nervous system that result in mental retardation and age-dependent Alzheimer-type neurodegeneration. Some of the neurodegenerative lesions, including A beta amyloid deposition, apoptotic cell death, and aberrant dendritic arborization, are in part due to constitutively increased expression of genes that encode the amyloid precursor protein, superoxide dismutase I, and S100-beta, and located within the Down locus. However, neurodegeneration in Down syndrome is also associated with aberrant expression of genes that are not linked to the Down locus, including the growth associated protein, GAP-43, nitric oxide synthase 3, neuronal thread protein, and pro-apoptosis genes such as p53, Bax, and interleukin-1 beta-converting enzyme. Increased expression of these non-Down locus genes correlates with proliferation of dystrophic neurites and apoptotic cell death, two important correlates of cognitive impairment in Alzheimer's disease. This article reviews the functional importance of abnormal gene expression in relation to Alzheimer-type neurodegeneration in brains of individuals with Down syndrome.
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PMID:Molecular abnormalities of the brain in Down syndrome: relevance to Alzheimer's neurodegeneration. 1066 65

Huperzine A, a promising therapeutic agent for Alzheimer's disease, was examined for its potential to antagonize the deleterious neurochemical, structural, and cognitive effects of infusing beta-amyloid protein-(1-40) into the cerebral ventricles of rats. Daily intraperitoneal administration of huperzine A for 12 consecutive days produced significant reversals of the beta-amyloid-induced deficit in learning a water maze task. This treatment also reduced the loss of choline acetyltransferase activity in cerebral cortex, and the neuronal degeneration induced by beta-amyloid protein-(1-40). In addition, huperzine A partly reversed the down-regulation of anti-apoptotic Bcl-2 and the up-regulation of pro-apoptotic Bax and P53 proteins and reduced the apoptosis that normally followed beta-amyloid injection. The present findings confirm that huperzine A can alleviate the cognitive dysfunction induced by intracerebroventricular infusion of beta-amyloid protein-(1-40) in rats. The beneficial effects are not confined to the cholinergic system, but also include favorable changes in the expression of apoptosis-related proteins and in the extent of apoptosis in widespread regions of the brain.
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PMID:Huperzine A attenuates cognitive dysfunction and neuronal degeneration caused by beta-amyloid protein-(1-40) in rat. 1151 30

Synaptic degeneration and death of neurons in limbic and cortical brain regions are the fundamental processes responsible for the manifestation of cognitive dysfunction and behavioural abnormalities in Alzheimer's disease (AD). Despite the various genetic and environmental factors, and the aging process itself that may lead to the manifestation of AD, multiple evidence from studies in experimental models and in AD brain tissue demonstrate that the underlying neurodegeneration is associated with morphological and biochemical features of apoptosis. At the cellular level, neuronal apoptosis in AD may be initiated by oxidative stress and related DNA damage, disruption of cellular calcium homeostasis, or endoplasmic reticulum (ER) stress. The molecular mechanisms of the biochemical cascades of apoptosis are beginning to be understood and involve upstream effectors such as Par-4, p53, and pro-apoptotic Bcl-2 family members, which mediate mitochondrial dysfunction and subsequent release of pro-apoptotic proteins, such as cytochrome c or apoptosis inducing factor (AIF), and subsequent caspase-dependent and -independent pathways which finally result in degradation of proteins and nuclear DNA. The regulation of apoptotic cascades is complex and involves transcriptional control as well as posttranscriptional protein modifications, such as protease-mediated cleavage, ubiquitination or poly(ADP-ribosylation). More recently, the regulation of protein phosphorylation by kinases and phosphatases is emerging as a prerequisite mechanism in the control of the apoptotic cell death program. A better understanding of the molecular underpinnings of neuronal apoptosis will lead to novel preventive and therapeutic approaches to the neurodegenerative processes in Alzheimer's disease and other neurological disorders where programmed cell death is prominent.
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PMID:Molecular insights into mechanisms of the cell death program: role in the progression of neurodegenerative disorders. 1701 59

Many studies reported that oxidative and nitrosative stress might be important for the pathogenesis of Alzheimer's disease (AD) beginning with arguably the earliest stage of AD, i.e., as mild cognitive impairment (MCI). p53 is a proapoptotic protein that plays an important role in neuronal death, a process involved in many neurodegenerative disorders. Moreover, p53 plays a key role in the oxidative stress-dependent apoptosis. We demonstrated previously that p53 levels in brain were significantly higher in MCI and AD IPL (inferior parietal lobule) compared to control brains. In addition, we showed that in AD IPL, but not in MCI, HNE, a lipid peroxidation product, was significantly bound to p53 protein. In this report, we studied by means of immunoprecipitation analysis, the levels of markers of protein oxidation, 3-nitrotyrosine (3-NT) and protein carbonyls, in p53 in a specific region of the cerebral cortex, namely the inferior parietal lobule, in MCI and AD compared to control brains. The focus of these studies was to measure the oxidation and nitration status of this important proapoptotic protein, consistent with the hypothesis that oxidative modification of p53 could be involved in the neuronal loss observed in neurodegenerative conditions.
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PMID:Effects of oxidative and nitrosative stress in brain on p53 proapoptotic protein in amnestic mild cognitive impairment and Alzheimer disease. 1843 34

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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PMID: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. 1849 39

Genistein and folic acid have been reported respectively to protect against the development of cognitive dysfunction; however, the underlying mechanism(s) for this protection remain unknown. In this report, the mechanism(s) contributing to the neuroprotective effects of genistein and folic acid were explored using rat cortical neuron cultures. We found that genistein and folic acid, both separately and collaboratively, increased cell viability and mitochondrial membrane potential in beta-amyloid (Abeta) 31-35-treated neurons. Furthermore, reduced percentage of comet cells and shortened tail length were observed in the neurons treated with genistein or folic acid. A more significant reduction in tail length of the comet neurons was observed in the co-administered neurons. RT-PCR analysis of the cultured cortical neurons showed down-regulated expression of p53, bax and caspase-3, but up-regulated expression of bcl-2 in the three neuroprotective treatment groups compared with neurons from the Abeta31-35 solo-treated group. In a nuclear dyeing experiment using Hoechst 33342, we found that both genistein and folic acid prevent neuronal apoptosis. Collectively, these findings suggest that the mechanism underlying the neuroprotection of genistein and folic acid singly or in combination observed in cultured cortical neuron studies might be related to their anti-apoptotic properties.
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PMID:Neuroprotective effects of genistein and folic acid on apoptosis of rat cultured cortical neurons induced by beta-amyloid 31-35. 1933 99

Mild cognitive impairment (MCI) is a syndrome defined as cognitive decline, but not sufficient to meet the criteria for any specific dementia. Although subjects with MCI may have an increased risk to develop AD, this clinical state encompasses several subtypes of cognitive dysfunction of different etiologies, none of which necessarily progresses to AD. The current inability of clinical criteria to accurately identify this at-risk group for AD development is fuelling the interest in biomarkers able to supplement clinical approaches. We recently described a blood-based cytofluorimetric method for conformationally altered p53 protein detection that allows the discrimination of AD patients from control subjects and patients affected by other dementias. The same protein also predicted progression to AD in preclinical patients with MCI two years before clinical diagnosis of AD was made. Herein, we describe these findings and discuss the potential of the test in diagnosing AD.
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PMID:Unfolded p53 in blood as a predictive signature signature of the transition from mild cognitive impairment to Alzheimer's disease. 2016

Oxidative stress caused by hydrogen peroxide (H(2)O(2)) plays an important role in the pathogenesis of Alzheimer's disease (AD). The prominent damages caused by H(2)O(2) include the ruin of membrane integrity, loss of intracellular neuronal glutathione (GSH), oxidative damage to DNA as well as the subsequent caspase-3 and p53 activation. Icariin is a flavonoid extracted from the traditional Chinese herb Epimedium brevicornum Maxim. We have previously reported that icariin has a good curative effect on patients with mild cognitive impairment (MCI), AD animal and cell models. However, the molecular mechanism of how icariin exerts neuroprotective effects is still not well understood. To address this question, we exposed undifferentiated neuronal cell lines (PC12 cells) to hydrogen peroxide (H(2)O(2)) and investigated the possible neuroprotective mechanisms of icariin. Vitamin E was used as a positive control. We observed that H(2)O(2) activated the JNK/p38 mitogen-activated protein kinase (MAPK) and induced PC12 cells apoptosis in a concentration-dependent manner. More over, we demonstrated that icariin protected PC12 cells by attenuating LDH leakage, reducing GSH depletion, preventing DNA oxidation damage and inhibiting subsequent activation of caspase-3 and p53, which are the main targets of H(2)O(2)-induced cell damage. In addition, we also found that icariin's neuroprotective effect may partly correlate with its inhibitory effect on JNK/p38 MAPK pathways. Therefore, our findings suggest that icariin is a candidate for a novel neuroprotective drug to against oxidative-stress induced neurodegeneration.
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PMID:Icariin inhibits hydrogen peroxide-induced toxicity through inhibition of phosphorylation of JNK/p38 MAPK and p53 activity. 2123 69

S-allyl cysteine (SAC), a sulfur containing amino acid derived from garlic, has been reported to have antioxidant, anti-cancer, antihepatotoxic and neurotrophic activity. This study was designed to examine the pre-treatment effects of SAC on cognitive deficits and oxidative damage in the hippocampus of intracerebroventricular streptozotocin (ICV-STZ)-infused mice. Mice pre-treated with SAC (30mg/kg) and vehicle (intraperitoneal; once daily for 15days) were bilaterally injected with ICV-STZ (2.57mg/kg body weight), whereas sham rats received the same volume of vehicle. The pre-treatment of this drug to Swiss albino mice has prevented the cognitive and neurobehavioral impairments. An increased latency and path length were observed in lesion, i.e. streptozotocin (STZ) group as compared to sham group and these were protected significantly in STZ group pre-treated with SAC. Levels of reduced glutathione (GSH) and its dependent enzymes (Glutathione peroxidase [GPx] and glutathione reductase [GR]) were decreased in STZ group as compared to sham group and pre-treatment of STZ group with SAC has protected their activities significantly. Conversely, the elevated level of thiobarbituric acid reactive substances (TBARS) in STZ group was attenuated significantly in SAC pre-treated group when compared with STZ lesioned group. Apoptotic parameters like DNA fragmentation, expression of Bcl2 and p53 were protected by the pre-treatment of SAC against STZ induced cognitive impairment. This study concludes that intervention of SAC could prevent free radicals associated deterioration of cognitive functions and neurobehavioral activities.
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PMID:S-allyl cysteine attenuates oxidative stress associated cognitive impairment and neurodegeneration in mouse model of streptozotocin-induced experimental dementia of Alzheimer's type. 2137 20

The identification and validation of biomarkers for preclinical patients with mild cognitive impairment (MCI) at-risk for Alzheimer's disease (AD) development is increasingly important. We used the cytofluorimetric analysis of unfolded p53 to determine the prognostic ability of the protein as predictive signature from MCI to AD in a longitudinal study of a population of presymptomatic patients with the clinical diagnosis of MCI. Venous blood samples from 24 healthy subjects, 28 MCI and 15 AD were analyzed with the cytofluorimetric method for unfolded p53 protein detection. Twenty-four MCI patients had clinical follow-up subsequent to the analysis for unfolded p53. Elevated levels of the conformationally altered protein were able to discriminate both MCI and AD patients comparing with healthy subjects. Longitudinal follow-up revealed that 7/24 MCI patients progressed to AD. All converters (100%) were predicted by elevated levels of unfolded p53, with a positive predictive value of 87.5%. These data support and extend our previous observation that the cytofluorimetric approach for unfolded p53 protein was able to discriminate AD patients from healthy subjects and to predict the progression from MCI to AD in presymptomatic patients before clinical diagnosis for AD was evident.
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PMID:Searching for predictive blood biomarkers: misfolded p53 in mild cognitive impairment. 2274 46


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