Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Biochemical and molecular mechanisms of neuronal cell death are currently an area of intense research. It is well documented that the lumbar spinal motoneurons of the chick embryo undergo a period of naturally occurring programmed cell death (PCD) requiring new gene expression and activation of caspases. To identify genes that exhibit changed expression levels in dying motoneurons, we used a PCR-based subtractive hybridization protocol to identify messages uniquely expressed in motoneurons deprived of trophic support as compared with their healthy counterparts. We report that one upregulated message in developing motoneurons undergoing cell death is the mRNA for amyloid precursor protein (APP). Increased levels of APP and beta-amyloid protein are also detected within dying motoneurons. The predicted peptide sequence of APP indicates two potential cleavage sites for caspase-3 (CPP-32), a caspase activated in dying motoneurons. When peptide inhibitors of caspase-3 are administered to motoneurons destined to undergo PCD, decreased levels of APP protein and greatly reduced beta-amyloid production are observed. Furthermore, we show that APP is cleaved by caspase-3. Our results suggest that differential gene expression results in increased levels of APP, providing a potential substrate for one of the cell death-activated caspases that may ultimately cause the demise of the cell. These results, combined with information on the toxic role of APP and its proteolytic by-product beta-amyloid, in the neurodegenerative disease Alzheimer's, suggest that events of developmental PCD may be reactivated in early stages of pathological neurodegeneration.
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PMID:Increased production of amyloid precursor protein provides a substrate for caspase-3 in dying motoneurons. 967 74

Recent studies have shown that deficient functioning of glutamate transporters (GTs) in Alzheimer disease (AD) might lead to neurodegeneration via excitotoxicity; however, the characteristics of cell death and pathways involved are not yet clear. The main objective of the present study was to determine if deficient GT functioning in AD could be associated with cell damage and caspase activation. For this purpose, we analyzed the levels of caspase-1 and 3 immunoreactivity in AD and control brains and correlated this data with the numbers of cells displaying DNA fragmentation, GT activity, and amyloid precursor protein (APP) mRNA expression. Compared to controls, AD cases showed extensive positive labeling of neurons and glial cells with an assay for DNA fragmentation suggestive of cell damage, as well as increased neuronal caspase-3 and Bcl-2 immunoreactivity. Linear regression analysis showed a strong negative correlation between GT activity and apoptosis, and between deficient GT functioning and caspase-3 immunoreactivity. Neurons displaying DNA fragmentation presented more intense caspase-3 immunoreactivity than intact neurons. In addition, the altered ratio between the spliced forms of APP correlated with DNA fragmentation and caspase-3 immunolabeling. Taken together, these results support the possibility that excitotoxic injury associated with deficient GT functioning and an imbalance in ratio of spliced APP forms might lead to cell death via caspase-3 activation.
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PMID:Caspase dependent DNA fragmentation might be associated with excitotoxicity in Alzheimer disease. 982 41

Forced overexpression of wild-type Alzheimer amyloid precursor protein (APP) causes postmitotic neurons to degenerate. Caspase-3 (CPP32) is a principal cell death protease involved in neuronal apoptosis during physiological development and under pathological conditions. Here, we investigated whether APP overexpression activates caspase-3 in human postmitotic neurons using adenovirus-mediated gene transfer. When a recombinant adenovirus vector expressing human wild-type APP695 was infected in vitro into neurally differentiated embryonal carcinoma NT2 cells, only postmitotic neurons underwent severe degeneration. Before neurodegeneration, full-length APP- and Abeta-immunoreactive peptides were accumulated in infected neurons, and caspase-3-like protease activity was markedly elevated. Western blot analysis revealed that activated caspase-3 subunits were generated in APP-accumulating neurons. Such neuronal caspase-3 activation was undetectable in NT2 neurons infected with beta-galactosidase-expressing adenovirus. Addition of the caspase-3 inhibitor acetyl-Asp-Glu-Val-Asp-aldehyde to the culture medium significantly reduced the severity of degeneration exhibited by APP-overexpressing neurons. Immunocytochemical analyses revealed that some APP-accumulating neurons contained activated caspase-3 subunits and exhibited the characteristics of apoptosis, such as chromatin condensation and DNA fragmentation. Activation of caspase-3 was also observed in vivo in rat hippocampal neurons infected with the APP-expressing adenovirus. These results suggest that wild-type APP is an intrinsic activator of caspase-3-mediated death machinery in postmitotic neurons.
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PMID:Activation of neuronal caspase-3 by intracellular accumulation of wild-type Alzheimer amyloid precursor protein. 1043 52

The familial Alzheimer's disease gene products, presenilin-1 and presenilin-2, have been reported to be functionally involved in amyloid precursor protein processing, notch receptor signaling, and programmed cell death or apoptosis. However, the molecular mechanisms by which presenilins regulate these processes remain unknown. With regard to the latter, we describe a molecular link between presenilins and the apoptotic pathway. Bcl-X(L), an anti-apoptotic member of the Bcl-2 family was shown to interact with the carboxyl-terminal fragments of PS1 and PS2 by the yeast two-hybrid system. In vivo interaction analysis revealed that both PS2 and its naturally occurring carboxyl-terminal products, PS2short and PS2Ccas, associated with Bcl-X(L), whereas the caspase-3-generated amino-terminal PS2Ncas fragment did not. This interaction was corroborated by demonstrating that Bcl-X(L) and PS2 partially co-localized to sites of the vesicular transport system. Functional analysis revealed that presenilins can influence mitochondrial-dependent apoptotic activities, such as cytochrome c release and Bax-mediated apoptosis. Together, these data support a possible role of the Alzheimer's presenilins in modulating the anti-apoptotic effects of Bcl-X(L).
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PMID:Interaction of Alzheimer's presenilin-1 and presenilin-2 with Bcl-X(L). A potential role in modulating the threshold of cell death. 1044 69

The amyloid beta-protein (A beta) pathologically accumulates in cerebral vascular and senile plaque deposits in the brains of patients with Alzheimer's disease (AD) and related disorders including hereditary cerebral hemorrhage with amyloidosis Dutch type (HCHWA-D). The cerebrovascular deposits are accompanied by degeneration and eventual loss of smooth muscle cells in cerebral vessel wall. Similarly, we have shown that pathogenic forms of A beta cause cell death in cultured human cerebrovascular smooth muscle (HCSM) cells in vitro. Here we show that pathogenic A beta induces a number of structural changes in HCSM cells including shrinkage of cell bodies, retraction of processes, disruption of the intracellular actin network, and nuclear condensation and fragmentation. These changes were accompanied by a number of biochemical alterations in the cells shown by in situ end labeling of nuclear DNA, proteolytic breakdown of smooth muscle cell a actin, and proteolytic activation of the proteinase caspase 3. Together, these characteristics are consistent with an apoptotic mechanism of cell death in HCSM cells in response to pathogenic A beta.
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PMID:Pathogenic amyloid beta-protein induces apoptosis in cultured human cerebrovascular smooth muscle cells. 1052 79

The role of the phosphatidylinositol-3 kinase pathway in the hyperphosphorylation of tau protein was investigated in cultured cells. Human kidney 293T-cells were cotransfected with tau and glycogen synthase kinase-3 (GSK-3) genes or tau and protein kinase B genes. The phosphorylation of tau protein was increased by cotransfection with GSK-3; however, it was decreased by cotransfection with protein kinase B. Human neuroblastoma SY5Y cells were treated with wortmannin, an inhibitor of phosphatidylinositol-3 kinase, and only transient (after 1 hour) activation of GSK-3 and hyperphosphorylation of tau protein were observed. However, continuous inactivation of protein kinase B was observed, suggesting the involvement of protein kinases other than protein kinase B in the phosphorylation and inactivation of GSK-3 after 3 hours. In cells treated with wortmannin, protein kinase C delta fragments were observed, and the protein kinase C activity increased after 3 hours, whereas treatment of cells with z-DEVD-fmk, an inhibitor of caspase-3, inhibited fragmentation of protein kinase C delta and induced continuous activation of GSK-3. It is suggested that fragmentation of protein kinase C delta during the process of apoptosis results in the phosphorylation and the inactivation of GSK-3. Those data suggest that, in Alzheimer disease, more complicated mechanisms are involved in the process of phosphorylation of tau protein predominantly regulated by P13K pathway.
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PMID:Significance of tau phosphorylation and protein kinase regulation in the pathogenesis of Alzheimer disease. 1085 Jul 26

A functional assay for proteolytic processing of the amyloid precursor protein (APP) was set up in yeast. This consisted of a membrane-bound chimeric protein containing the beta-secretase cleaved C-terminal fragment of APP fused to the Ga14 transcription factor. Using this chimera in a GAL-reporter yeast strain, an expression library of human cDNAs was screened for clones that could activate the GAL-reporter genes by proteolytic processing of the membrane-bound APP-Gal4. Two human proteases, caspase-3 and caspase-8, were identified and confirmed to act by a mechanism that involved proteolysis at the site in the APP-Gal4 chimera that corresponded to the natural caspase cleavage site in APP, thus linking a readily scorable phenotype to proteolytic processing of APP. The activation of caspase-3 involved a mechanism that was independent of aspartic acid residue 175 at the cleavage site normally required for processing of caspase-3.
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PMID:A yeast genetic assay for caspase cleavage of the amyloid-beta precursor protein. 1091 20

Alzheimer's disease (AD) is characterized by the deposition in brain of beta-amyloid (Abeta) peptides, elevated brain caspase-3, and systemic deficiency of cytochrome c oxidase. Although increased Abeta deposition can result from mutations in amyloid precursor protein or presenilin genes, the cause of increased Abeta deposition in sporadic AD is unknown. Cytoplasmic hybrid ("cybrid") cells made from mitochondrial DNA of nonfamilial AD subjects show antioxidant-reversible lowering of mitochondrial membrane potential (delta(gYm), secrete twice as much Abeta(1-40) and Abeta(1-42), have increased intracellular Abeta(1-40) (1.7-fold), and develop Congo red-positive Abeta deposits. Also elevated are cytoplasmic cytochrome c (threefold) and caspase-3 activity (twofold). Increased AD cybrid Abeta(1-40) secretion was normalized by inhibition of caspase-3 or secretase and reduced by treatment with the antioxidant S(-)pramipexole. Expression of AD mitochondrial genes in cybrid cells depresses cytochrome c oxidase activity and increases oxidative stress, which, in turn, lowers delta(psi)m. Under stress, cells with AD mitochondrial genes are more likely to activate cell death pathways, which drive caspase 3-mediated Abeta peptide secretion and may account for increased Abeta deposition in the AD brain. Therapeutic strategies for reducing neurodegeneration in sporadic AD can address restoration of delta(psi)m and reduction of elevated Abeta secretion.
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PMID:Alzheimer's disease cybrids replicate beta-amyloid abnormalities through cell death pathways. 1093 64

Apoptotic cell death has been implicated in Alzheimer's disease pathology and amyloid peptide induced neurotoxicity. We investigated the survival promoting effects of Propentofylline in two models of apoptotic cell death, nerve growth factor withdrawal and beta-amyloid mediated cell death in nerve growth factor differentiated rat pheochromocytoma cell lines. The increase in cell death as measured by lactate dehydrogenase release in response to nerve growth factor withdrawal was suppressed by nitric oxide donor S-nitroso-N-acetylpenicillamine (12.5 to 200 microM) and by 8-bromoguanosine-3',5'-cyclic monophosphate (1.25 to 10mM). Both agents decreased cell death mediated by 25 microM beta-amyloid, suggesting that the protective mechanism involves guanosine -3', 5'-cyclic monophosphate. In support of this hypothesis we can show that S-nitroso-N-acetylpenicillamine increases intracellular levels of guanosine -3',5'-cyclic monophosphate in pheochromocytoma cell lines 3 to 8 fold.Propentofylline, a phosphodiesterase inhibitor, has previously demonstrated neuroprotective activity in stroke models and is a potential candidate for therapeutic treatment in neurodegenerative diseases. The present findings support this claim by providing evidence that Propentofylline has protective effects in both nerve growth factor withdrawal and beta-amyloid mediated cell death. Lactate dehydrogenase release was significantly reduced and caspase-3-like activity was attenuated after cotreatment with Propentofylline. Furthermore Propentofylline dose responsively increases intracellular guanosine-3',5'-cyclic monophosphate levels over the same dose range that provided protection. We hypothesized that guanosine-3',5'-cyclic monophosphate is a key mediator of neuroprotection under these conditions.
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PMID:Guanosine 3',5'-cyclic monophosphate mediated inhibition of cell death induced by nerve growth factor withdrawal and beta-amyloid: protective effects of propentofylline. 1097 37

To elucidate the mechanism of neuronal death in Alzheimer's disease, we investigated the effects of overexpression of wild-type Alzheimer amyloid precursor protein (APP) on neuronal cells and glial cells in vivo. When an APP695-expressing adenovirus was injected into the dorsal hippocampal region, a number of neurons in remote areas were positively stained with anti-APP monoclonal antibody, and underwent severe degeneration from 3 to 7 days after viral inoculation. Most degenerating neurons were immunopositive with both APP and activated caspase-3, but some neurons that expressed activated caspase-3 were not expressing APP from 7 to 14 days after virus injection. In the neighborhood of the degenerating neurons, activated microglia/macrophages, which were identified by the phenotypic marker C3bi receptor (CD11b/c; OX-42), were observed, and some of them appeared to phagocytose the caspase-3-immunopositive degenerating neurons. In addition to microglia/macrophages, infiltrating leukocytes expressing CD45 or CD4 were also detected. These results suggest that the increased accumulation of APP induced not only caspase-3-mediated death machinery, but also inflammatory responses including microglial activation. These inflammatory responses might cause further neurodegeneration through the alternative pathway that might activate the caspase-3-mediated death machinery without APP expression.
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PMID:Caspase-3 activation and inflammatory responses in rat hippocampus inoculated with a recombinant adenovirus expressing the Alzheimer amyloid precursor protein. 1103 54


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