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 p3 peptide [amyloid beta-peptide (Abeta) 17-40/42], derived by alpha- and gamma-secretase cleavage of the amyloid precursor protein (APP), is a major constituent of diffuse plaques in Alzheimer's disease and cerebellar pre-amyloid in Down's syndrome. However, the importance of p3 peptide accumulation in Alzheimer's disease and its toxic properties is not clear. Here, we demonstrate that treatment of cells with Abeta 17-42 leads to apoptosis in two human neuroblastoma cell lines, SH-SY5Y and IMR-32. Abeta 17-42 activated caspase-8 and caspase-3, induced poly(ADP-ribose) polymerase cleavage, but did not activate caspase-9. Selective caspase-8 and caspase-3 inhibitors completely blocked Abeta 17-42-induced neuronal death. Abeta 17-42 moderately activated c-Jun N-terminal kinase (JNK); however, overexpression of a dominant-negative mutant of SEK1, the upstream kinase of JNK, protected against Abeta 17-42 induced neuronal death. These results demonstrate that Abeta 17-42 induced neuronal apoptosis via a Fas-like/caspase-8 activation pathway. Our findings reveal the previously unrecognized toxic effect of Abeta 17-42. We propose that Abeta 17-42 constitutes an additional toxic peptide derived from APP proteolysis and may thus contribute to the neuronal cell loss characteristic of Alzheimer's disease.
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PMID:Abeta 17-42 in Alzheimer's disease activates JNK and caspase-8 leading to neuronal apoptosis. 1218 49

The Abeta deposition in the neuritic plaques is one of the major neuropathological hallmarks of the Alzheimer disease (AD). Studies in vitro have demonstrated that the Abeta[25-35] fragment, which contains the cytotoxic functional sequence of the amyloid peptide, induces neurotoxicity and cell death by apoptosis. Despite intense investigations, a complete picture of the precise molecular cascade leading to cell death in a single cellular model is still lacking. In this study, we provide evidence that Abeta[25-35] induce apoptosis either alone or in presence of iron in peripheral blood lymphocytes cells (PBL) in a concentration-dependent fashion by an oxidative stress mechanism involving: (1) the production of hydrogen peroxide (H2O2), reflected by rhodamine-positive fluorescent cells, (2) activation and/or translocation of NF-kappaB, p53 and c-Jun transcription factors showed by immunocytochemical diaminobenzidine positive nuclei, (3) activation of NF-kappaB complex by electrophoretic mobility shift assay/immuno-blotting/and ammonium pyrrolidinedithiocarbamate (PDTC) inhibition, (4) caspase-3 activation, reflected by caspase Ac-DEVD-cho inhibition, (5) mRNA synthesis de novo according to actinomycin D cell death inhibition. These results are consistent with the notion that the Abeta[25-35]/H2O2 generation precede the apoptotic process and that once H2O2 is generated, it is able to trigger a specific cell death signalisation. Thus, taken together these results, we present a well-ordered cascade of the major molecular events leading PBL to apoptosis. These results may contribute to explain the importance of Abeta alone or in the presence of redox-available iron in association with Abeta plaques (and neurofibrillary tangles) in AD brains and the significant role played by H2O2 as a second messenger of death signal in some degenerative diseases linked to oxidative stress stimuli.
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PMID:Abeta[25-35] peptide and iron promote apoptosis in lymphocytes by an oxidative stress mechanism: involvement of H2O2, caspase-3, NF-kappaB, p53 and c-Jun. 1238 62

Amyloid beta peptide (Abeta) is a neurotoxic metabolic product of the amyloid precursor protein (APP). Abeta is strongly implicated in the pathology of Alzheimer's disease (AD) and can be formed intracellularly. In this study, we show that the addition of Abeta to isolated mouse brain mitochondria can directly induce cytochrome c (Cyt c) release and mitochondrial swelling, which were partially inhibited by cyclosporin A (CsA). These results suggest that the Abetaaccumulated intracellularly by APP processing might exert neurotoxicity by interacting with mitochondria and inducing mitochondrial swelling and release of Cyt c, which activates caspase-3 and finally can lead to apoptosis in neuronal cells and to neurodegeneration in AD.
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PMID:Amyloid beta peptide induces cytochrome C release from isolated mitochondria. 1239 6

Caspase-3 mediated cleavage of the amyloid precursor protein (APP) has been proposed as a putative mechanism underlying amyloidosis and neuronal cell death in Alzheimer's disease (AD). We utilized an antibody that selectively recognizes the neo epitope generated by caspase-3 mediated cleavage of APP (alphadeltaC(csp)-APP) to determine if this proteolytic event occurs in senile plaques in the inferior frontal gyrus and superior temporal gyrus of autopsied AD and age-matched control brains. Consistent with a role for caspase-3 activation in AD pathology, alphadeltaC(csp)-APP immunoreactivity colocalized with a subset of TUNEL-positive pyramidal neurons in AD brains. AlphadeltaC(csp)-APP immunoreactivity was found in neurons and glial cells, as well as in small- and medium-size particulate elements, resembling dystrophic terminals and condensed nuclei, respectively, in AD and age-matched control brains. There were a larger number of alphadeltaC(csp)-APP immunoreactive elements in the inferior frontal gyrus and superior temporal gyrus of subjects with AD pathology than age-matched controls. AlphadeltaC(csp)-APP immunoreactivity in small and medium size particulate elements were the main component colocalized with 30% of senile plaques in the inferior frontal gyrus and superior temporal gyrus of AD brains. In some control brains, alphadeltaC(csp)-APP immunoreactivity appeared to be associated with a clinical history of metabolic encephalopathy. Our results suggest that apoptosis contributes to cell death resulting from amyloidosis and plaque deposition in AD.
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PMID:Caspase-cleaved amyloid precursor protein in Alzheimer's disease. 1240 29

We have previously reported that overexpression of wild-type amyloid precursor protein (APP) in postmitotic neurons induces cleavage-dependent activation of caspase-3 both in vivo and in vitro. In this study, we investigated the mechanism underlying APP-induced caspase-3 activation using adenovirus-mediated gene transfer into postmitotic neurons derived from human embryonal carcinoma NT2 cells. Overexpression of wild-type APP significantly increased intracellular (45)Ca(2+) content prior to the activation of caspase-3 in NT2-derived neurons. Chelation of intracellular Ca(2+) markedly suppressed APP-induced activation of caspase-3. Furthermore, calpain, a Ca(2+)-dependent cysteine protease, was activated in neurons overexpressing APP as assessed by increased levels of calpain-cleaved alpha-fodrin and autolytic mu-calpain fragments. Neither calpain nor caspase-3 was activated in neurons expressing an APP mutant defective in the Abeta(1-20) domain. Calpain inhibitors almost completely suppressed APP-induced activation of neuronal caspase-3. E64d, a membrane permeable inhibitor of calpain, significantly suppressed APP-induced neuronal death. These results suggest that overexpression of wild-type APP activates calpain that mediates caspase-3 activation in postmitotic neurons.
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PMID:Activation of calpain in cultured neurons overexpressing Alzheimer amyloid precursor protein. 1242 45

Aged garlic extract (AGE) contains several neuroactive compounds, including S-allyl-L-cysteine (SAC) and allixin. We characterized cell death induced by amyloid beta-protein (Abeta), 4-hydroxynonenal (HNE), tunicamycin, an endoplasmic reticulum (ER) stressor, or trophic factor deprivation, and investigated whether and how SAC could prevent this in nerve growth factor (NGF)-differentiated PC12 cells, a model of neuronal cells. Exposure of the cells to amyloid beta-protein(1-40) (Abeta(1-40)) decreased the extent of [3-(4,5)-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium (MTT) reduction activity and loss of neuronal integrity, but these effects were not prevented by Ac-DEVD-CHO, a caspase-3 inhibitor. Simultaneously applied SAC protected the cells against Abeta-induced cell death in a concentration-dependent manner. It also protected them against tunicamycin-induced neuronal death. In contrast, it afforded no protection against cell death induced by HNE and trophic factor deprivation, which is mediated by a caspase-3-dependent pathway. These results suggest that SAC may selectively protect cell death induced by Abeta and tunicamycin, which may be triggered by ER dysfunction in NGF-differentiated PC12 cells.
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PMID:Protective effect of S-allyl-L-cysteine, a garlic compound, on amyloid beta-protein-induced cell death in nerve growth factor-differentiated PC12 cells. 1272 18

The amyloid precursor protein (APP) is a transmembrane protein whose abnormal processing is associated with the pathogenesis of Alzheimer's disease. In this study, we examined the expression and role of cell-associated APP in primary dorsal root ganglion (DRG) neurons. When dissociated DRG cells prepared from mouse embryos were treated with nerve growth factor (NGF), neuronal APP levels were transiently elevated. DRG neurons treated with an antibody against cell surface APP failed to mature and underwent apoptosis. When NGF was withdrawn from the cultures after a 36-h NGF treatment, virtually all neurons underwent apoptosis by 48 h. During the course of apoptosis, some neurons with intact morphology contained increased levels of APP immunoreactivity, whereas the APP levels were greatly reduced in apoptotic neurons. Furthermore, affected neurons contained immunoreactivities for activated caspase-3, a caspase-cleaved APP fragment (APPDeltaC31), and Abeta. Downregulation of endogenous APP expression by treatment with an APP antisense oligodeoxynucleotide significantly increased the number of apoptotic neurons in NGF-deprived DRG cultures. Furthermore, overexpression of APP by adenovirus vector-mediated gene transfer reduced the number of apoptotic neurons deprived of NGF. These results suggest that endogenous APP is upregulated to exert an antiapoptotic effect on neurotrophin-deprived DRG neurons and subsequently undergoes caspase-dependent proteolysis.
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PMID:Upregulation and antiapoptotic role of endogenous Alzheimer amyloid precursor protein in dorsal root ganglion neurons. 1274 53

The mechanism by which beta-amyloid protein (A beta) causes degeneration in cultured neurons is not completely understood, but several lines of evidence suggest that A beta-mediated neuronal death is associated with an enhanced production of reactive oxygen species (ROS) and oxidative damage. In the present study, we address whether supplementation of glucose-containing culture media with energy substrates, pyruvate plus malate (P/M), protects rat primary neurons from A beta-induced degeneration and death. We found that P/M addition attenuated cell death evoked by beta-amyloid peptides (A beta(25-35) and A beta(1-40)) after 24 hr treatment and that this effect was blocked by alpha-ciano-3-hydroxycinnamate (CIN), suggesting that it requires mitochondrial pyruvate uptake. P/M supply to control and A beta-treated neuronal cultures increases cellular reducing power, as indicated by the ability to reduce the dye 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). The early increases in ROS levels, measured by dichlorofluorescein (DCF) fluorescence, and caspase-3 activity that follow exposure to A beta were notably reduced in the presence of P/M. These results place activation of caspase-3 most likely downstream of oxidative damage to the mitochondria and indicate that mitochondrial NAD(P) redox status plays a central role in the neuroprotective effect of pyruvate. Inhibition of respiratory chain complexes and mitochondrial uncoupling did not block the early increase in ROS levels, suggesting that A beta could initiate oxidative stress by activating a source of ROS that is not accesible to the antioxidant defenses fueled by mitochondrial substrates.
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PMID:Pyruvate protection against beta-amyloid-induced neuronal death: role of mitochondrial redox state. 1283 69

Glaucoma is a chronic neurodegeneration of the optic nerve and one of the leading causes of vision loss in the world among the aging. Retinal ganglion cells (RGCs) have been shown to die by apoptosis, or programmed cell death. Central to apoptosis is the activation of specific proteases, termed caspases. Caspases are activated in chronic neurodegenerations such as Alzheimer's disease (AD) as well as in RGCs after optic nerve transection. In rat glaucoma models we have shown that caspase-3, a major effector of the apoptotic cascade, is activated in RGCs and cleaves amyloid precursor protein (APP) to produce neurotoxic fragments that include amyloid-beta. Caspase-8, which initiates apoptosis after activation of receptors of the tumor necrosis factor (TNF) superfamily, is also activated in RGCs. This suggests a new hypothesis for RGC death in glaucoma involving chronic amyloid-beta neurotoxicity, mimicking AD at the molecular level. With loss of the protective effect of APP and upregulation of toxic APP fragments, RGCs die from chronic caspase activation, loss of synaptic homeostasis, amyloid-beta cytotoxicity and excitotoxicity. The benefits are that treatments for AD could be used to treat glaucoma, and strategies developed to treat glaucoma could treat other neurodegenerations.
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PMID:Glaucoma: ocular Alzheimer's disease? 1295 57

S-allyl-L-cysteine (SAC), one of the organosulfur compounds found in aged garlic extract, has been shown to possess various biological effects including neurotrophic activity. In our previous experiments, we found that SAC could protect against amyloid beta-protein (Abeta)- and tunicamycin-induced cell death in differentiated PC12 cells. In the study described here, we characterized the neuronal death induced by Abeta, 4-hydroxynonenal (HNE), tunicamycin, and trophic factor deprivation, and investigated whether and how SAC could prevent this in cultured rat hippocampal neurons. Treatment with SAC protected these cells against Abeta- and tunicamycin-induced neuronal death, which is mediated predominantly through caspase-12-dependent pathway in a concentration-dependent manner. In contrast, it afforded no protection against HNE- and trophic factor-deprivation-induced cell death, which has been shown to be mediated by caspase-3-dependent pathway. SAC also attenuated the Abeta-induced increase of intracellular reactive oxygen species in hippocampal neurons. SAC had no effect on Abeta-induced cell death in cultured cerebellar granule neurons, which was prevented by a caspase-3 inhibitor. These results suggest that SAC could protect against the neuronal cell death that is triggered by ER dysfunction in the hippocampus, and that it has no effect on neuronal cell death that is dependent upon the caspase-3 mediated pathway.
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PMID:S-allyl-L-cysteine selectively protects cultured rat hippocampal neurons from amyloid beta-protein- and tunicamycin-induced neuronal death. 1464 58


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