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

The activation of caspase-3 and possibly other caspases during apoptosis may lead to the cleavage of the amyloid precursor protein (APP) and subsequent accumulation of APP cleavage products (cAPP). We examined the association between activated caspase-3 and cAPP in human brain by qualitative and quantitative analysis of in situ immunohistochemistry and Western blots. Frontal cortex and hippocampal tissue from age-matched control and Alzheimer's brains (AD) was used. Both activated caspase-3 and cAPP are increased in AD [Braak and Braak (BB) stage IV-VI] compared to aged control (BB stage 0-1) and transitional (BB stage II-III) cases in the hippocampal and frontal cortex. Caspase-3 activation and the accumulation of APP cleavage fragments appear to either parallel or precede neurofibrillary tangle formation. These findings raise the possibility that the activation of caspase-3 and cleavage of APP may be involved with neuronal degeneration and that pathways characteristic of apoptosis are activated in AD.
 ...
PMID:Accumulation of caspase cleaved amyloid precursor protein represents an early neurodegenerative event in aging and in Alzheimer's disease. 1467 56

1. Recent studies indicate that neuronal loss in Alzheimer's disease (AD) is accompanied by the deposition of beta-amyloid protein (A beta) in senile plaques. Nicotine as a major component of cigarette smoke has been suggested to have a protective effect for neurons against A beta neurotoxicity. 2. Our present study demonstrates that nicotine protected cultured hippocampal neurons against the A beta-induced apoptosis. Nicotine effectively inhibits apoptosis in hippocampal cultures caused by A beta(25-35) or A beta(1-40) treatment and increase of caspase activity induced by A beta(25-35) or A beta(1-40). 3. Measurements of cellular oxidation and intracellular free Ca(2+) showed that nicotine suppressed A beta-induced accumulation of free radical and increase of intracellular free Ca(2+). 4. Cholinergic antagonist mecamylamine inhibited nicotine-induced protection against A beta-induced caspase-3 activation and ROS accumulation. 5. The data show that the protection of nicotine is partly via nicotinic receptors. Our results suggest that nicotine may be beneficial in retarding the neurodegenerative diseases such as AD.
 ...
PMID:Nicotine attenuates beta-amyloid peptide-induced neurotoxicity, free radical and calcium accumulation in hippocampal neuronal cultures. 1475 1

Abstract Alzheimer's disease is widely held to be associated with oxidative stress due, in part, to the membrane action of beta-amyloid peptide aggregates. Here, we studied the effect of cannabidiol, a major non-psychoactive component of the marijuana plant (Cannabis sativa) on beta-amyloid peptide-induced toxicity in cultured rat pheocromocytoma PC12 cells. Following exposure of cells to beta-amyloid peptide (1 micro g/mL), a marked reduction in cell survival was observed. This effect was associated with increased reactive oxygen species (ROS) production and lipid peroxidation, as well as caspase 3 (a key enzyme in the apoptosis cell-signalling cascade) appearance, DNA fragmentation and increased intracellular calcium. Treatment of the cells with cannabidiol (10(-7)-10(-4)m) prior to beta-amyloid peptide exposure significantly elevated cell survival while it decreased ROS production, lipid peroxidation, caspase 3 levels, DNA fragmentation and intracellular calcium. Our results indicate that cannabidiol exerts a combination of neuroprotective, anti-oxidative and anti-apoptotic effects against beta-amyloid peptide toxicity, and that inhibition of caspase 3 appearance from its inactive precursor, pro-caspase 3, by cannabidiol is involved in the signalling pathway for this neuroprotection.
 ...
PMID:Neuroprotective effect of cannabidiol, a non-psychoactive component from Cannabis sativa, on beta-amyloid-induced toxicity in PC12 cells. 1503 Mar 97

Mounting evidence indicates increased susceptibility to cell death and increased oxidative damage as common features in neurons from sporadic Alzheimer's disease (AD) patients but also from familial AD (FAD) cases. Autosomal dominant forms of FAD are caused by mutations of the amyloid precursor protein (APP) gene and by mutations of the genes encoding for presenilin 1 or presenilin 2 (PS1/2). We investigated the effect of the Swedish APP double mutation (APPsw) on oxidative stress-induced cell death mechanisms in PC12 cells. This mutation results in from three- to sixfold increased beta-amyloid (Abeta) production compared with wild-type APP (APPwt). Because APPsw cells secrete low Abeta levels similar to the situation in FAD brains, our cell model represents a very suitable approach to elucidate the AD-specific cell death pathways under more likely physiological conditions. We found that APPsw-bearing cells show decreased mitochondrial membrane potential after exposure to hydrogen peroxide. In addition, activity of the executor caspase 3 after treatment with hydrogen peroxide was elevated in APPsw cells, which seems to be the result of an enhanced activation of both intrinsic and extrinsic apoptosis pathways. Our findings provide evidence that the massive neurodegeneration in early age of FAD patients could be a consequence of an increased vulnerability of neurons by mitochondrial abnormalities resulting in activation of different apoptotic pathways as a consequence to elevated oxidative stress levels. Finally, we propose a hypothetical sequence of the pathogenic steps linking sporadic AD, FAD, Abeta production, mitochondrial dysfunction with caspase pathway, and neuronal loss.
 ...
PMID:Increased apoptotic cell death in sporadic and genetic Alzheimer's disease. 1503

Alzheimer's disease (AD) brain reveals high rates of oxygen consumption and oxidative stress, altered antioxidant defences, increased oxidized polyunsaturated fatty acids, and elevated transition metal ions. Mitochondrial dysfunction in AD is perhaps relevant to these observations, as such may contribute to neurodegenerative cell death through the formation of reactive oxygen species (ROS) and the release of molecules that initiate programmed cell death pathways. In this study, we analyzed the effects of beta-amyloid peptide (Abeta) on human teratocarcinoma (NT2) cells expressing endogenous mitochondrial DNA (mtDNA), mtDNA from AD subjects (AD cybrids), and mtDNA from age-matched control subjects (control cybrids). In addition to finding reduced cytochrome oxidase activity, elevated ROS, and reduced ATP levels in the AD cybrids, when these cell lines were exposed to Abeta 1-40 we observed excessive mitochondrial membrane potential depolarization, increased cytoplasmic cytochrome c, and elevated caspase-3 activity. When exposed to Abeta, events associated with programmed cell death are activated in AD NT2 cybrids to a greater extent than they are in control cybrids or the native NT2 cell line, suggesting a role for mtDNA-derived mitochondrial dysfunction in AD degeneration.
 ...
PMID:Mitochondria dysfunction of Alzheimer's disease cybrids enhances Abeta toxicity. 1518 44

Plaques composed of amyloid beta (Abeta) have been found within days following brain trauma in humans, similar to the hallmark plaque pathology of Alzheimer's disease (AD). Here, we evaluated the potential source of this Abeta and long-term mechanisms that could lead to its production. Inertial brain injury was induced in pigs via head rotational acceleration of 110 degrees over 20 ms in the coronal plane. Animals were euthanized at 3 hours, 3 days, 7 days, and 6 months post-injury. Immunohistochemistry and Western blot analyses of the brains were performed using antibodies specific for amyloid precursor protein (APP), Abeta peptides, beta-site APP-cleaving enzyme (BACE), presenilin-1 (PS-1), caspase-3, and caspase-mediated cleavage of APP (CCA). Substantial co-accumulation for all of these factors was found in swollen axons at all time points up to 6 months following injury. Western blot analysis of injured brains confirmed a substantial increase in the protein levels of these factors, particularly in the white matter. These data suggest that impaired axonal transport due to trauma induces long-term pathological co-accumulation of APP with BACE, PS-1, and activated caspase. The abnormal concentration of these factors may lead to APP proteolysis and Abeta formation within the axonal membrane compartment.
 ...
PMID:Long-term accumulation of amyloid-beta, beta-secretase, presenilin-1, and caspase-3 in damaged axons following brain trauma. 1527 12

The amyloid beta peptide (Abeta) is generated by subsequent cleavages by beta- and gamma-secretases. Therefore, these two enzymes are putative therapeutic targets to prevent Abeta production, and hopefully to slow down or even stop the Alzheimer's disease (AD) neurodegenerative process. Several studies have revealed that gamma-secretase hydrolyses other important substrates besides beta-amyloid precursor protein (betaAPP) thus adding another level of complexity to designing fully AD-specific interfering drugs. Here we demonstrate that three distinct presenilin-directed gamma-secretase inhibitors as well as JLK compounds indirectly potentiate caspase 3 activity, the effector caspase of the apoptotic cascade. Thus, inhibitors were shown to drastically stimulate caspase 3 activity in wild-type mice blastocyst-derived and fibroblast cells. Interestingly, some of these inhibitors known to interact with presenilins also trigger caspase activation in presenilin-deficient cells. However, inhibitors do not affect recombinant caspase 3 activity, indicating that the effect on this enzyme was indirect. Furthermore, we established that caspase 3 activation was not due to an effect of gamma-secretase inhibitors on calpains, a family of proteolytic enzymes able to modulate caspase 3 activity. Altogether, our data demonstrate that presenilin-directed gamma-secretase inhibitors affect caspase 3 activity in a presenilin-independent manner. Therefore, as presenilin-dependent gamma-secretase activity is not specific for betaAPP and because its inhibitors clearly affect other vital cell functions, care should be taken in considering 'gamma-secretase' inhibitors as putative therapeutic tools to interfere with AD pathology.
 ...
PMID:Presenilin-directed inhibitors of gamma-secretase trigger caspase 3 activation in presenilin-expressing and presenilin-deficient cells. 1528 85

The authors describe a homogeneous, high-throughput screening (HTS) assay for measuring protease activity and detection of inhibitors. The assay comprises a cyclic beta-galactosidase (beta-gal) enzyme donor peptide (ED) containing a protease-selective cleavage sequence. Alone, the cyclic peptide is inactive, but when linearized following protease cleavage, ED complements with beta-gal enzyme acceptor forming active beta-gal enzyme. This then catalyzes the formation of either fluorescent or chemiluminescent products, with beta-gal turnover providing a highly amplified signal, and thus an assay technology of high sensitivity. To demonstrate the utility of the technology, an EFC assay was developed to measure the activity of 2, caspase 3 and beta-secretase. Using a cyclic ED containing the caspase 3 substrate sequence, DEVD, the EFC assay signal was linear with respect to caspase 3 concentration. The assay was very sensitive, being able to detect activity at low picogram amounts of caspase 3. For the beta-secretase (BACE) EFC assay, a cyclic ED containing the Swedish mutant cleavage site of amyloid precursor protein (APP), SEVNLDAEFK, was used. In a similar fashion to the caspase 3 assay, the signal induced by BACE activity was linear with respect to enzyme concentration and was highly sensitive, being able to detect nanogram quantities of BACE. The assay was also more sensitive than a commercially available FRET-based assay of BACE activity. It is concluded that the EFC protease assay is a simple, flexible, and sensitive technology for HTS of proteases.
 ...
PMID:Beta galactosidase enzyme fragment complementation as a high-throughput screening protease technology. 1529 39

Abeta (beta-amyloid) peptides are found aggregated in the cortical amyloid plaques associated with Alzheimer's disease neuropathology. Inhibition of the proteasome alters the amount of Abeta produced from APP (amyloid precursor protein) by various cell lines in vitro. Proteasome activity is altered during aging, a major risk factor for Alzheimer's disease. In the present study, a human neuroblastoma cell line expressing the C-terminal 100 residues of APP (SH-SY5Y-SPA4CT) was used to determine the effect of proteasome inhibition, by lactacystin and Bz-LLL-COCHO (benzoyl-Leu-Leu-Leu-glyoxal), on APP processing at the gamma-secretase site. Proteasome inhibition caused a significant increase in Abeta peptide levels in medium conditioned by SH-SY5Y-SPA4CT cells, and was also associated with increased cell death. APP is a substrate of the apoptosis-associated caspase 3 protease, and we therefore investigated whether the increased Abeta levels could reflect caspase activation. We report that caspase activation was not required for proteasome-inhibitor-mediated effects on APP (SPA4CT) processing. Cleavage of Ac-DEVD-AMC (N-acetyl-Asp-Glu-Val-Asp-7-amino-4-methylcoumarin), a caspase substrate, was reduced following exposure of SH-SY5Y-SPA4CT cells to lactacystin, and co-treatment of cells with lactacystin and a caspase inhibitor [Z-DEVD-FMK (benzyloxycarbonyl-Val-Ala-DL-Asp-fluoromethylketone)] resulted in higher Abeta levels in medium, augmenting those seen with lactacystin alone. This study indicated that proteasome inhibition could increase APP processing specifically at the gamma-secretase site, and increase release of Abeta, in the absence of caspase activation. This indicates that the decline in proteasome function associated with aging would contribute to increased Abeta levels.
 ...
PMID:Proteasome-mediated effects on amyloid precursor protein processing at the gamma-secretase site. 1547 68

Hyperphosphorylated tau in neurites surrounding beta-amyloid (betaA) deposits, as revealed with phospho-specific anti-tau antibodies, are found in amyloid precursor protein (APP) Tg2576 mice. Because betaA is a source of oxidative stress and may be toxic for cultured cells, the present study examines the expression of phosphorylated (active) stress-activated kinase c-Jun N-terminal kinase (SAPK/JNK-P) and p38 kinase (p38-P), which have the capacity to phosphorylate tau at specific sites, and their specific substrates c-Jun and ATF-2, which are involved in cell death and survival in several paradigms, in Tg2576 mice. The study was planned to shed light about the involvement of these kinases in tau phosphorylation in cell processes surrounding amyloid plaques, as well as in the possible phosphorylation (activation) of c-Jun and activating transcription factor-2 (ATF-2) in relation to betaA deposition. Moderate increase in the expression of phosphorylated mitogen-activated protein kinase and extracelullar signal-regulated kinase (MAPK/ERK-P) occurs in a few amyloid plaques. However, strong expression of SAPK/JNK-P and p38-P is found in the majority of, if not all, amyloid plaques, as seen in serial consecutive sections stained for betaA and stress kinases. Moreover, confocal microscopy reveals colocalization of phospho-tau and SAPK/JNK-P, and phospho-tau and p38-P in many dystrophic neurites surrounding amyloid plaques. Increased expression levels of nonbound tau, SAPK/JNK-P and p38-P are corroborated by Western blots of total cortical homogenate supernatants in Tg2576 mice when compared with age-matched controls. No increase in phosphorylated c-JunSer63 (c-Jun-P) and ATF-2Thr71 (ATF-2-P) is found in association with betaA deposits. In addition, no expression of active (cleaved) caspase-3 (17 kDa) has been found in transgenic mice. Taken together, these observations provide a link between betaA-induced oxidative stress, activation of stress kinases SAPK/JNK and p38, and tau hyperphosphorylation in neurites surrounding amyloid plaques, but activation of these kinases is not associated with accumulation of c-Jun-P and ATF-2-P, nor with activation of active caspase-3 in the vicinity of betaA deposits.
 ...
PMID:Expression of stress-activated kinases c-Jun N-terminal kinase (SAPK/JNK-P) and p38 kinase (p38-P), and tau hyperphosphorylation in neurites surrounding betaA plaques in APP Tg2576 mice. 1548 25


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>