Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.56 (caspase-3)
 35,750 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Swedish double mutation (KM670/671NL) of amyloid precursor protein (APPsw) is associated with early-onset familial Alzheimer's disease (FAD) and results in from three- to sixfold increased beta-amyloid production. The goal of the present study was to elucidate the effects of APPsw on mechanisms of apoptotic cell death. Therefore, PC12 cells were stably transfected with human APPsw. Here we report that the vulnerability of APPsw-bearing PC12 cells to undergo apoptotic cell death was significantly enhanced after exposure to hydrogen peroxide compared to human wild-type APP-bearing cells, empty vector-transfected cells, and parent untransfected cells. In addition, we have analyzed the potential influence of several mechanisms that can interfere with the execution of the apoptotic cell death program: the inhibition of cell death by the use of caspase inhibitors and the reduction of oxidative stress by the use of (+/-)-alpha-tocopherol (vitamin E). Interestingly, oxidative stress-induced cell death was significantly attenuated in APPsw PC12 cells by pretreatment with caspase-3 inhibitors but not with caspase-1 inhibitors. In parallel, caspase-3 activity was markedly elevated in APPsw PC12 after stimulation with hydrogen peroxide for 6 hr, whereas caspase-1 activity was unaltered. In addition, oxidative stress-induced cell death could be reduced after pretreatment of APPsw cells with (+/-)-alpha-tocopherol. The protective potency of (+/-)-alpha-tocopherol was even greater than that of caspase-3 inhibitors. Our findings further emphasize the role of mutations in the amyloid precursor protein in apoptotic cell death and may provide the fundamental basis for further efforts to elucidate the underlying processes caused by FAD-related mutations.
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PMID:Elevated vulnerability to oxidative stress-induced cell death and activation of caspase-3 by the Swedish amyloid precursor protein mutation. 1128 46

The brain's response to ischemia, which helps determine clinical outcome after stroke, is regulated partly by competing genetic programs that respectively promote cell survival and delayed cell death. Many genes involved in this response have been identified individually or systematically, providing insights into the molecular basis of ischemic injury and potential targets for therapy. The development of microarray systems for gene expression profiling permits screening of large numbers of genes for possible involvement in biological or pathological processes. Therefore, we used an oligodeoxynucleotide-based microarray consisting of 374 human genes, most implicated previously in apoptosis or related events, to detect alterations in gene expression in the hippocampus of rats subjected to 15 minutes of global cerebral ischemia followed by up to 72 hours of reperfusion. We found 1.7-fold or greater increases in the expression of 57 genes and 1.7-fold or greater decreases in the expression of 34 genes at 4, 24, or 72 hours after ischemia. The number of induced genes increased from 4 to 72 hours, whereas the number of repressed genes decreased. The induced genes included genes involved in protein synthesis, genes mutated in hereditary human diseases, proapoptotic genes, antiapoptotic genes, injury-response genes, receptors, ion channels, and enzymes. We detected transcriptional induction of several genes implicated previously in cerebral ischemia, including ALG2, APP, CASP3, CLU, ERCC3, GADD34, GADD153, IGFBP2, TIAR, VEGF, and VIM, as well as other genes not so implicated. We also found coinduction of several groups of related genes that might represent functional modules within the ischemic neuronal transcriptome, including VEGF and its receptor, NRP1; the IGF1 receptor and the IGF1-binding protein IGFBP2; Rb, the Rb-binding protein E2F1, and the E2F-related transcription factor, TFDP1; the CACNB3 and CACNB4 beta-subunits of the voltage-gated calcium channel; and caspase-3 and its substrates, ACINUS, FEM1, and GSN. To test the hypothesis that genes identified through this approach might have roles in the pathophysiology of cerebral ischemia, we measured expression of the products of two induced genes not heretofore implicated in cerebral ischemia-GRB2, an adapter protein involved in growth-factor signaling pathways, and SMN1, which participates in RNA processing and is deleted in most cases of spinal muscular atrophy. Western analysis showed enhanced expression of both proteins in hippocampus at 24 to 72 hours after ischemia, and SMN1 was localized by immunohistochemistry to hippocampal neurons. These results suggest that microarray analysis of gene expression may be useful for elucidating novel molecular mediators of cell death and survival in the ischemic brain.
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PMID:Microarray analysis of hippocampal gene expression in global cerebral ischemia. 1145 15

In the present study, we evaluated the time-course of caspase-3 activation, and the evolution of cell death following focal cerebral ischemia produced by transient middle cerebral artery occlusion in rats. Ischemia-induced active caspase-3 immunoreactivity in the striatum but not the cortex at 3 and 6 h time points post-reperfusion. Furthermore, using a novel approach to visualize enzymatic activity, deltaC-APP, a C-terminal cleavage product of APP generated by caspase-3, was found to immunolocalize to the same areas as active caspase-3. Double-labeling studies demonstrated co-localization of these two proteins at the cellular level. Further double-labeling experiments revealed that active caspase-3 was confined to neuronal cells which were still viable and thus immunoreactive for NeuN. DNA fragmentation, assessed histologically by terminal dUTP nick-end labeling (TUNEL), was observed in a small number of cells in the striatum as early as 3 h, but only began to appear in the cortex by 6 h. DNA fragmentation was progressive, and by 24 h post-reperfusion, large portions of both the striatum and cortex showed TUNEL positive cells. However, double-labeling of active caspase-3 with TUNEL showed only minimal co-localization at all time-points. Thus, caspase-3 activation is an event that appears to occur prior to DNA fragmentation. As a confirmation of the histological TUNEL data, 24 h ischemia also induced the generation of nucleosome fragments, evidenced by cell death enzyme-linked immunosorbent assay. Using a novel ischemia-induced substrate cleavage biochemical approach, spectrin P120 fragment, a caspase-specific cleavage product of alpha II spectrin, a cytoskeletal protein, was shown to be elevated by western blotting. Brain concentrations of both nucleosomes and spectrin P120 correlate with the degree of injury previously assessed by triphenyltetrazolium chloride staining and infarct volume calculation. Together, our findings suggest a possible association between caspase-3 activation and ischemic cell death following middle cerebral artery occlusion brain injury.
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PMID:Immunohistochemical and biochemical assessment of caspase-3 activation and DNA fragmentation following transient focal ischemia in the rat. 1240 27

Mutations in the APP gene lead to enhanced cleavage by the beta- and gamma-secretase, and increased Abeta formation, which are tightly associated with Alzheimer's disease (AD)-like neuropathological changes. To examine whether depositions of Abeta by APP mutations are increased, and if this is associated with potential pathogenic phenotypes, the APPsw was expressed in a transgenic line under the control of the neuron-specific enolase (NSE) promoter. A behavioral dysfunction was shown at 12 months, and intensive staining bands, with APP and Abeta-42 antibodies, were visible in the brains of transgenic mice. Of the MAPK family, both JNK and p38 were activated in the brains of transgenic mice, whereas there was no significant activation of the ERK. In parallel, tau phosphorylation was also enhanced in the transgenic relative to the control mice. Moreover, the Cox-2 levels, from Western blot and immunostaining, were increased in the brains of the transgenic line. Furthermore, there were significant caspase-3- and TUNEL-stained nuclei in the transgenic line compared to the age-matched control mice. Thus, these results suggest that NSE-controlled APPsw transgenic mice appear to be a more relevant model in neuropathological phenotypes of AD, and thus could be useful in developing new therapeutic treatments for targeting the aberrant phenotypes that appear in these mice.
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PMID:Aberrant expressions of pathogenic phenotype in Alzheimer's diseased transgenic mice carrying NSE-controlled APPsw. 1498 Aug 7

Neurons of the hippocampal dentate gyrus selectively undergo programmed cell death in patients suffering from bacterial meningitis and in experimental models of pneumococcal meningitis in infant rats. In the present study, a membrane-based organotypic slice culture system of rat hippocampus was used to test whether this selective vulnerability of neurons of the dentate gyrus could be reproduced in vitro. Apoptosis was assessed by nuclear morphology (condensed and fragmented nuclei), by immunochemistry for active caspase-3 and deltaC-APP, and by proteolytic caspase-3 activity. Co-incubation of the cultures with live pneumococci did not induce neuronal apoptosis unless cultures were kept in partially nutrient-deprived medium. Complete nutrient deprivation alone and staurosporine independently induced significant apoptosis, the latter in a dose-response way. In all experimental settings, apoptosis occurred preferentially in the dentate gyrus. Our data demonstrate that factors released by pneumococci per se failed to induce significant apoptosis in vitro. Thus, these factors appear to contribute to a multifactorial pathway, which ultimately leads to neuronal apoptosis in bacterial meningitis.
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PMID:Apoptosis of hippocampal neurons in organotypic slice culture models: direct effect of bacteria revisited. 1521 89

Huperzine A (HupA), isolated from Chinese herb Huperzia serrata, is a potent, highly specific and reversible inhibitor of acetylcholinesterase. It has been found to reverse or attenuate cognitive deficits in a broad range of animal models. Clinical trials in China have demonstrated that HupA significantly relieves memory deficits in aged subjects, patients with benign senescent forgetfulness, Alzheimer's disease (AD) and vascular dementia (VD), with minimal peripheral cholinergic side effects compared with other AChEIs in use. HupA possesses the ability to protect cells against hydrogen peroxide, beta-amyloid protein (or peptide), glutamate, ischemia and staurosporine-induced cytotoxicity and apoptosis. These protective effects are related to its ability to attenuate oxidative stress, regulate the expression of apoptotic proteins Bcl-2, Bax, P53 and caspase-3, protect mitochondria, and interfere with APP metabolism. Antagonizing effects on NMDA receptors and potassium currents may contribute to the neuroprotection as well. It is also possible that the non-catalytic function of AChE is involved in neuroprotective effects of HupA. The therapeutic effects of HupA on AD or VD are probably exerted via a multi-target mechanism.
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PMID:Neuroprotective effects of huperzine A. A natural cholinesterase inhibitor for the treatment of Alzheimer's disease. 1595 16

The recent therapeutic approach in which drug candidates are designed to possess diverse pharmacological properties and act on multiple targets has stimulated the development of several multifunction drugs. These include ladostigil (TV3326) [(N-propargyl-(3R) aminoindan-5yl)-ethyl methyl carbamate], which combines the pharmacophore-neuroprotective effects of rasagiline, a selective monoamine oxidase (MAO)-B inhibitor, with the cholinesterase (ChE) inhibitory activity of rivastigmine or iron chelating moiety such as M30. In the case of M30 the pharmacophore of brain permeable iron chelator VK-28 plus the MAO inhibitor-neuroprotective propargylamine moiety of rasagiline are combined in a single molecule as a potential treatment for Alzheimer's disease, Lewy body disease, and Parkinson's disease with dementia. Here, we discuss the activities of ladostigil in terms of its cholinesterase cognitive enhancing potential, antiParkinson, antidepressant, neuroprotection and APP (amyloid precursor protein) processing potential. One major attribute of ladostigil is its neuroprotective activity in neuronal cell cultures and in vivo. Employing an apoptotic model of neuroblastoma SK-N-SH cells, the molecular mechanism of its neuroprotective activity has been determined. The current studies show that ladostigil significantly decreased apoptosis via inhibition of the cleavage and prevention of caspase-3 activation through a mechanism related to regulation of the Bcl-2 family proteins, resulting in reduced levels of Bad and Bax and induced levels of Bcl-2. In addition, ladostigil elevated the levels of pPKC(pan). We have also followed the regulation of APP processing and found that ladostigil markedly decreased apoptotic-induced levels of holo-APP, as well as stimulated the release of the non-amyloidogenic soluble APP (sAPPalpha) into the conditioned medium via a established protein kinsae C-MAPkinase dependent pathway. Similar to ladostigil, its S-isomer, TV3279, which is a ChE inhibitor lacking MAO inhibitory activity, exerted similar neuroprotective properties and APP processing, suggesting that the mode of action is independent of MAO inhibition. These effects were shown to reside in the propargylamine moiety. These findings indicate that the dual actions of the anti-apoptotic-neuroprotective activity and the ability to modulate APP processing, could make ladostigil a potentially valuable drug for the treatment of Alzheimer's disease.
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PMID:Implications of co-morbidity for etiology and treatment of neurodegenerative diseases with multifunctional neuroprotective-neurorescue drugs; ladostigil. 1719 68

Previous studies have identified that progesterone may be neuroprotective following traumatic brain injury (TBI). However, most of these have utilized models of TBI that produce a focal lesion or a significant ischemic component, neither of which is necessarily present in diffuse TBI. The current study uses a model of diffuse TBI in rats to examine the effects of progesterone on morphological changes and functional outcome following TBI. Male and ovariectomized female rats were subject to severe impact-acceleration injury under halothane anesthesia. After injury, animals were given a physiological, subcutaneous dose of progesterone (1.67 mg/kg) or equal volume of vehicle (sesame oil) daily throughout a 9-day neurologic assessment period where functional outcome was assessed using the rotarod and Barnes maze tests. There was a similar post-injury performance of male and ovariectomized female animals. Post-injury administration of progesterone improved the motor and cognitive performance of ovariectomized and male animals compared to vehicle-treated controls. Morphological differences between these animals, such as dark cell change, caspase-3 and APP immunoreactivity, were also investigated. Progesterone-treated males showed comparatively less dead or dying neurons, and marked attenuation of caspase-3 immunoreactivity. Both ovariectomized female and male animals treated with progesterone showed a profound reduction in axonal injury (seen via diminished APP immunoreactivity) when compared to controls. We conclude that physiological concentrations of progesterone administered after diffuse TBI confers beneficial effects on morphologic and functional outcome in both ovariectomized female and male animals.
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PMID:Effects of progesterone on neurologic and morphologic outcome following diffuse traumatic brain injury in rats. 1736 36

The presenilin (PS)-dependent gamma-secretase activity refers to a high molecular mass-complex including, besides PS1 or PS2, three other proteins recently identified, namely nicastrin, Aph-1, and Pen-2. This proteolytic complex has been shown to contribute to both gamma- and epsilon-cleavages of the beta-amyloid precursor protein (betaAPP), thereby generating beta-amyloid peptides (Abeta) and the APP intracellular domain (AICD), respectively. TMP21, a member of the p24 cargo protein family, was recently shown to interact with PS complexes. Interestingly, TMP21 modulates gamma-secretase-mediated Abeta production but does not regulate epsilon-secretase-derived AICD formation [F. Chen, H. Hasegawa, G. Schmitt-ulms, T. Kawarai, C. Bohm, T. Katayama, Y. Gu, N. Sanjo, M. Glista, E. Rogaeva, Y. Wakutami, R. Pardossi-Piquard, X. Ruan, A. Tandon, F. Checler, P. Marambaud, K. Hansen, D. Westaway, P. St. George-Hyslop, P. Fraser, TMP21 is a presenilin complex component that modulates gamma- but not epsilon-secretase activities, Nature 440 (2006) 1208-1212]. Here we investigate the functional incidence of the over-expression or depletion of TMP21 on both intracellular and secreted Abeta recoveries and AICD-associated phenotypes. First we confirm that TMP21 depletion yields increased levels of secreted Abeta40. However, we demonstrate that both staurosporine-stimulated caspase-3 activation, p53 and neprilysin expression and activity were not affected by TMP21 over-expression or depletion. Overall, our functional data further reinforce the view that TMP21 behaves as a regulator of gamma- but not epsilon-cleavages generated by PS-dependent gamma-secretase complex.
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PMID:TMP21 regulates Abeta production but does not affect caspase-3, p53, and neprilysin. 1840 62

Mechanisms of neuronal loss in Alzheimer's disease (AD) are poorly understood. Here we show that apoptosis is a major form of neuronal cell death in PS/APP mice modeling AD-like neurodegeneration. Pyknotic neurons in adult PS/APP mice exhibited apoptotic changes, including DNA fragmentation, caspase-3 activation, and caspase-cleaved alpha-spectrin generation, identical to developmental neuronal apoptosis in wild-type mice. Ultrastructural examination using immunogold cytochemistry confirmed that activated caspase-3-positive neurons also exhibited chromatin margination and condensation, chromatin balls, and nuclear membrane fragmentation. Numbers of apoptotic profiles in both cortex and hippocampus of PS/APP mice compared with age-matched controls were twofold to threefold higher at 6 months of age and eightfold higher at 21 to 26 months of age. Additional neurons undergoing dark cell degeneration exhibited none of these apoptotic features. Activated caspase-3 and caspase-3-cleaved spectrin were abundant in autophagic vacuoles, accumulating in dystrophic neurites of PS/APP mice similar to AD brains. Administration of the cysteine protease inhibitor, leupeptin, promoted accumulation of autophagic vacuoles containing activated caspase-3 in axons of PS/APP mice and, to a lesser extent, in those of wild-type mice, implying that this pro-apoptotic factor is degraded by autophagy. Leupeptin-induced autophagic impairment increased the number of apoptotic neurons in PS/APP mice. Our findings establish apoptosis as a mode of neuronal cell death in aging PS/APP mice and identify the cross talk between autophagy and apoptosis, which influences neuronal survival in AD-related neurodegeneration.
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PMID:Neuronal apoptosis and autophagy cross talk in aging PS/APP mice, a model of Alzheimer's disease. 1868 38


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