Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.23.5 (cathepsin D)
4,130 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The accumulation and localization of cathepsins E and D in the rat hippocampus and neostriatum during the neurodegenerating process induced by transient forebrain ischemia were investigated by immunoprecipitation and by immunohistochemistry using discriminative antibodies specific for each enzyme. While significant amounts of cathepsin D were found in both the hippocampus and the neostriatum of normal rats, cathepsin E was barely detectable in these tissues. No significant change in their levels was found in these tissues of postischemic rats for up to 3 days after transient forebrain ischemia. After 7 days of the treatment, cathepsin E was markedly increased in both tissues. Although the cathepsin D content in these tissues was also increased at this stage, the rate of increase was much less than that of cathepsin E. At the light microscopic level, the increased immunoreactivity for each enzyme was mainly found in reactive glial cells and degenerating neurons in the hippocampal CA1 subfield at 7 days postischemia. In the neostriatal dorsolateral portion, cathepsin D immunoreactivity was also increased in both reactive glial cells and degenerating neurons, whereas increased immunoreactivity of cathepsin E was only identified in reactive glial cells at 7 days postischemia. It was also found by double-immunostaining technique that the cathepsin E-positive glial cells were largely reactive microglial cells, whereas the cathepsin D-positive glial cells were associated mainly with reactive astrocytes. These results suggest that the accumulation of both cathepsins E and D in the regions of selective neuronal vulnerability may be associated with the postischemic development of intense gliosis and also probably neurodegenerative responses.
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PMID:Transient forebrain ischemia induces increased expression and specific localization of cathepsins E and D in rat hippocampus and neostriatum. 833 72

Combining immunocytochemistry with in situ hybridization of Alzheimer disease (AD) hippocampus demonstrated a 50% reduction in grain density for synaptophysin message over CA1 pyramidal neurons containing neurofibrillary tangles (NFT) relative to near neighbor NFT-free neurons. This decrease was not global, but was selective since message grain density for the lysosomal protein, cathepsin D, increased 33% in these neurons (relative to NFT-free neurons). Poly A+ message grain density decreased by 25% in NFT neurons. Percent of the cell body containing NFT correlated -0.35 (p < 0.0001) with grain density for synaptophysin message. These data verify the concept of altered profiles of gene expression as a function of disease state within single cells and suggest that events associated with NFT formation may lead to altered expression of synaptic messages.
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PMID:Quantitative decrease in synaptophysin message expression and increase in cathepsin D message expression in Alzheimer disease neurons containing neurofibrillary tangles. 1019 19

The possibility that brain aging in rats exhibits regional variations of the type found in humans was studied using lysosomal chemistry as a marker. Age-related (two vs 12months; male Sprague-Dawley) differences in cathepsin D immunostaining were pronounced in the superficial layers of entorhinal cortex and in hippocampal field CA1, but not in neocortex and field CA3. Three changes were recorded: an increase in the intraneuronal area occupied by labeled lysosomes; clumping of immunopositive material within neurons; more intense cytoplasmic staining. Western blot analyses indicated that the increases involved the active forms of cathepsin D rather than their proenzyme. Shrinkage of cathepsin-D-positive neuronal cell bodies was observed in entorhinal cortex but not in neocortical sampling zones. Age-related lysosomal changes as seen with cathepsin B immunocytochemistry were considerably more subtle than those obtained with cathepsin D antibodies. In contrast, a set of glial and/or vascular elements located in a distal dendritic field of the middle-aged hippocampus was much more immunoreactive for cathepsin B than cathepsin D. The areas exhibiting sizeable changes in the present study are reported to be particularly vulnerable to aging in humans. The results thus suggest that aspects of brain aging common to mammals help shape neurosenescence patterns in humans.
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PMID:Regionally selective changes in brain lysosomes occur in the transition from young adulthood to middle age in rats. 1079 71

The pathogenesis of neurofibrillary tangles (NFTs) in Alzheimer's disease (AD) is poorly understood, but changes in the expression of specific messenger RNAs (mRNAs) may reflect mechanisms underlying the formation of NFTs and their consequences in affected neurons. For these reasons, we compared the relative abundance of multiple mRNAs in tangle-bearing versus normal CA1 neurons aspirated from sections of AD and control brains. Amplified antisense RNA expression profiling was performed on individual isolated neurons for analysis of greater than 18,000 expressed sequence tagged complementary DNAs (cDNAs) with cDNA microarrays, and further quantitative analyses were performed by reverse Northern blot analysis on 120 selected mRNAs on custom cDNA arrays. Relative to normal CA1 neurons, those harboring NFTs in AD brains showed significant reductions in several classes of mRNAs that are known to encode proteins implicated in AD neuropathology, including phosphatases/kinases, cytoskeletal proteins, synaptic proteins, glutamate receptors, and dopamine receptors. Because cathepsin D mRNA was upregulated in NFT-bearing CA1 neurons in AD brains, we performed immunohistochemical studies that demonstrated abundant cathepsin D immunoreactivity in the same population of tangle-bearing CA1 neurons. In addition, levels of mRNAs encoding proteins not previously implicated in AD were reduced in CA1 tangle-bearing neurons, suggesting that these proteins (eg, activity-regulated cytoskeleton-associated protein, focal adhesion kinase, glutaredoxin, utrophin) may be novel mediators of NFT formation or degeneration in affected neurons. Thus, the profile of mRNAs differentially expressed by tangle-bearing CA1 neurons may represent a "molecular fingerprint" of these neurons, and we speculate that mRNA expression profiles of diseased neurons in AD may suggest new directions for AD research or identify novel targets for developing more effective AD therapies.
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PMID:Expression profile of transcripts in Alzheimer's disease tangle-bearing CA1 neurons. 1089 19

Cathepsin D is a lysosomal enzyme involved in neuronal degeneration. In this study, the immunohistochemistry of cathepsin D was studied in hippocampal CA1 neurons that are vulnerable to ischemia, and parahippocampal glial cells. CA1 neurons from the majority of cases showed cathepsin D immunoreactivity in the cytoplasm, whereas shrunk neurons were unstained in only one case. There was no statistically significant correlation between the postmortem interval between death and autopsy, and cathepsin D immunoreactivity in CA1 neurons. These observations indicate that cathepsin D immunoreactivity is not a sensitive marker for neuronal degeneration or postmortem changes. On the other hand, there was a statistically significant correlation between age and cathepsin D immunoreactivity in the cytoplasm of parahippocampal glial cells. This shows that senescence is correlated with cathepsin D expression in humans as has been reported previously in an animal study.
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PMID:An immunohistochemical study on cathepsin D in human hippocampus. 1109 76

This study reports that postischemic apoptotic cell death of the hippocampal cornu ammonis (CA) 1 neurons is delayed in aged gerbils. Age-related changes in the process of CA1 neuronal death following transient ischemia was studied. Two groups of Mongolian gerbils were used in this study, which compared adult (4-month-old) and aged (24-month-old) animals by hematoxylin-eosin stain, in situ nick-end labeling (TUNEL method) and electron microscopy. In the process of neuronal death, neuronal loss of the aged group was histologically less severe than that of the adult group. TUNEL-positive cells were found on days 3-5 after ischemia in the adult group, while they were still found on day 7 in the aged group. The apoptotic process of the aged group was delayed compared to the adult group. Furthermore, lipofuscin was ultrastructurally observed inside the apoptotic body 5 days after ischemia in CA1 pyramidal neurons of the aged group. It is likely that colocalization of lysosomal enzyme cathepsin D with lipofuscin might be associated with the age-related alteration of lysosomal system in the neurons. Altogether these data suggest that age-related lysosomal changes might affect the apoptotic cascade process in postischemic CA1 neurons.
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PMID:Age-related changes of cornu ammonis 1 pyramidal neurons in gerbil transient ischemia. 1113 39

In the last decade, the molecular mechanisms of apoptosis, a major type of active cell death (type I cell death) have largely been clarified in mammalian cells. Particularly, the caspase family of proteinases has been shown to play crucial roles in the execution of apoptosis. Differing from apoptosis, type II cell death is known to be associated with autophagosomes/autolysosomes and appear in the developing nervous system (CLARKE, 1990). We have previously shown that delayed neuronal death occurring in the CA1 pyramidal layer of the gerbil hippocampus after brief forebrain ischemia is apoptotic in nature and autophagosomes/autolysosomes abundantly appear in the neurons before DNA fragmentation. To further understand the roles of autophagosomes/autolysosomes in active cell death, we examined the apoptosis of PC12 cells using morphological and biochemical techniques. PC12 cells are known to undergo apoptosis when cultured in the absence of serum. In such an environment, the mitochondrial pathway of apoptosis is activated; cytochrome c is released from mitochondria, and caspase-9/caspase-3 are activated. We have first examined morphological features of PC12 cells during the apoptotic process following serum deprivation, and found that autophagy is induced from the early stage of the process in the cells before typical nuclear changes. When autophagy is inhibited in the cells by 3-methyladenine, an autophagy inhibitor, they are largely protected from apoptosis. In relation to the induction of autophagy in PC12 cells following serum deprivation, immunoreactivity, protein amounts, and the proteolytic activity of lysosomal proteinases, particularly cathepsins B and D, are all greatly altered; those of cathepsin B drastically decrease in the cells from the early stage of serum-deprived cultures, whereas those of cathepsin D increase. Moreover, PC12 cells overexpressing cathepsin D undergo apoptosis more rapidly in serum-deprived cultures than wild-type cells, whereas those overexpressing cathepsin B increase the viability. These lines of evidence suggest that autophagy is involved in PC12 cell death following serum deprivation, this type of cell death being regulated by lysosomal proteinases, cathepsins B and D, downstream autophagy.
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PMID:Autophagic cell death and its execution by lysosomal cathepsins. 1157 20

The regional, cellular, and subcellular localization of phosphorylated p38 MAPK (pp38) was examined by immunocytochemistry, immuofluorescent multiple labeling, and immunoblotting of extracts as well as immunoprecipitates of human postmortem tissue from control and Alzheimer's disease (AD) cases at different Braak stages. "Early AD" cases (Braak stages IV-V) and a subset of Braak stage VI cases have high levels of pp38 immunoreactivity, with the most dense immunoreactivity located in CA2 and subiculum followed by CA1 in the hippocampus. On the contrary, very little pp38 was detected in age-matched controls (Braak stages 0-II). More importantly, as revealed by various multiple labeling experiments, pp38 immunoreactivity is mainly located in neurons bearing early neurofibrillary pathology, but not in typically fibrillar tangles that are densely stained by thioflavin-S. Most pp38-positive neurons only contain a small amount of phospho-tau. Additionally, pp38 immunoreactivity was not associated with senile plaques. At the subcellular level, pp38-immunoreactive granules are usually larger than the granules stained with the lysosomal marker cathepsin D. Immunoblotting with different extraction buffers and immunoprecipitation indicate that pp38 does not or only loosely binds to phospho-tau. Taken together, this study demonstrates that p38 MAPK is activated at early stages of neurofibrillary degeneration in AD hippocampus. The p38 activation may also be linked to neurodegeneration through mechanisms other than neurofibrillary tangle formation.
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PMID:P38 MAP kinase is activated at early stages in Alzheimer's disease brain. 1455 67

The major neuropathological features of the transmissible spongiform encephalopathies (TSEs) are well documented, however, the underlying molecular events are poorly defined. We have applied cDNA expression arrays and quantitative RT-PCR to the study of gene expression in the brain, and more specifically in the hippocampus, of the well-characterized ME7/CV mouse model of scrapie. The number of genes showing consistent, scrapie-associated changes in expression was limited, and was primarily restricted to glial-associated genes. Increased expression of genes encoding glial fibrillary acidic protein, vimentin, complement component 1q (alpha and beta polypeptides), cathepsin D, clusterin and cystatin C was evident in the hippocampus from 170 days after inoculation (dpi), with expression increasing thereafter to terminal disease (225-235 dpi). Elevation of gene expression preceded clinical disease by approximately 30 days, and coincided with a 20-day period in the ME7/CV model during which 50% of the CA1 hippocampal neurones are lost. Increased expression of cystatin C, an inhibitor of lysosomal cysteine proteases, is a novel finding in the context of TSE neuropathology and was confirmed by Western analysis and immunocytochemistry.
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PMID:Identification of up-regulated genes by array analysis in scrapie-infected mouse brains. 1548 32

The multiplicity of cell death mechanisms induced by neonatal hypoxia-ischemia makes neuroprotective treatment against neonatal asphyxia more difficult to achieve. Whereas the roles of apoptosis and necrosis in such conditions have been studied intensively, the implication of autophagic cell death has only recently been considered. Here, we used the most clinically relevant rodent model of perinatal asphyxia to investigate the involvement of autophagy in hypoxic-ischemic brain injury. Seven-day-old rats underwent permanent ligation of the right common carotid artery, followed by 2 hours of hypoxia. This condition not only increased autophagosomal abundance (increase in microtubule-associated protein 1 light chain 3-11 level and punctuate labeling) but also lysosomal activities (cathepsin D, acid phosphatase, and beta-N-acetylhexosaminidase) in cortical and hippocampal CA3-damaged neurons at 6 and 24 hours, demonstrating an increase in the autophagic flux. In the cortex, this enhanced autophagy may be related to apoptosis since some neurons presenting a high level of autophagy also expressed apoptotic features, including cleaved caspase-3. On the other hand, enhanced autophagy in CA3 was associated with a more purely autophagic cell death phenotype. In striking contrast to CA3 neurons, those in CA1 presented only a minimal increase in autophagy but strong apoptotic characteristics. These results suggest a role of enhanced autophagy in delayed neuronal death after severe hypoxia-ischemia that is differentially linked to apoptosis according to the cerebral region.
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PMID:Enhancement of autophagic flux after neonatal cerebral hypoxia-ischemia and its region-specific relationship to apoptotic mechanisms. 1981 6


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