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排序方式: 共有113条查询结果,搜索用时 18 毫秒
81.
Koriyama H Kouchi Z Umeda T Saido TC Momoi T Ishiura S Suzuki K 《Cellular signalling》1999,11(11):831-838
Protein kinase C (PKC) family members play pivotal roles in cellular signal transduction and nPKCdelta and theta are known to be subjected to restrictive proteolysis during apoptosis. Here we show that nPKCepsilon was specifically cleaved and generates 43-kDa and 36-kDa C-terminal fragments during chemotherapeutic drug-induced apoptosis. The proteolytic cleavage of nPKCdelta and epsilon was completely inhibited by pretreatment with Ac-DEVD-cho, a specific inhibitor of caspase-3 family enzymes. Furthermore, nPKCepsilon in non-treated U937 cell lysates was cleaved by purified recombinant caspase-3 to generate the 43-kDa fragment, identical in size to the fragment observed in vivo. This cleavage was prevented by the addition of Ac-DEVD-cho. These results suggest that caspase-3 specifically cleaves nPKCepsilon. These findings suggest the possibility that nPKC subfamily members are generally involved in the execution of apoptosis but they are regulated diversely depending on the different apoptotic stimuli. 相似文献
82.
Hiroki Sasaguri Per Nilsson Shoko Hashimoto Kenichi Nagata Takashi Saito Bart De Strooper John Hardy Robert Vassar Bengt Winblad Takaomi C Saido 《The EMBO journal》2017,36(17):2473-2487
Animal models of human diseases that accurately recapitulate clinical pathology are indispensable for understanding molecular mechanisms and advancing preclinical studies. The Alzheimer's disease (AD) research community has historically used first‐generation transgenic (Tg) mouse models that overexpress proteins linked to familial AD (FAD), mutant amyloid precursor protein (APP), or APP and presenilin (PS). These mice exhibit AD pathology, but the overexpression paradigm may cause additional phenotypes unrelated to AD. Second‐generation mouse models contain humanized sequences and clinical mutations in the endogenous mouse App gene. These mice show Aβ accumulation without phenotypes related to overexpression but are not yet a clinical recapitulation of human AD. In this review, we evaluate different APP mouse models of AD, and review recent studies using the second‐generation mice. We advise AD researchers to consider the comparative strengths and limitations of each model against the scientific and therapeutic goal of a prospective preclinical study. 相似文献
83.
H Koike H Seki Z Kouchi M Ito T Kinouchi S Tomioka H Sorimachi T C Saido K Maruyama K Suzuki S Ishiura 《Journal of biochemistry》1999,126(1):235-242
We developed an assay method using a novel quenched fluorescent substrate (QFS) flanking the beta-cleavage site of amyloid precursor protein (APP), and purified a candidate beta-secretase from bovine brain. N-terminal amino acid analysis showed the candidate to be thimet oligopeptidase (TOP). The cDNA for human TOP was cloned from a human brain cDNA library and expressed in COS cells. The enzyme was further purified on a Ni2+-agarose column. TOP cleaved the Swedish Alzheimer's substrate (SEVNLDAEFR) as well as the normal substrate (SEVKMDAEFR). We then coexpressed TOP with APP695 in COS cells, collected transfected cells and conditioned media, and analyzed them by immunoblotting. The antibody against the specific secreted APP cleaved by beta-secretase (sAPPbeta) detected the secretion of sAPPbeta only from APP/hTOP-overexpressing cells, and not from cells overexpressing of antisense hTOP cDNA. Finally, we analyzed the immunolocalization of overexpressed hTOP in COS cells. Most hTOP was localized in the nuclei, but a small amount was localized in the Golgi or other organelles around the nuclei. These results suggest that TOP has a beta-secretase-like activity responsible for the processing of APP. 相似文献
84.
Calpastatin is up-regulated in response to hypoxia and is a suicide substrate to calpain after neonatal cerebral hypoxia-ischemia. 总被引:22,自引:0,他引:22
K Blomgren U Hallin A L Andersson M Puka-Sundvall B A Bahr A McRae T C Saido S Kawashima H Hagberg 《The Journal of biological chemistry》1999,274(20):14046-14052
In a model of cerebral hypoxia-ischemia in the immature rat, widespread brain injury is produced in the ipsilateral hemisphere, whereas the contralateral hemisphere is left undamaged. Previously, we found that calpains were equally translocated to cellular membranes (a prerequisite for protease activation) in the ipsilateral and contralateral hemispheres. However, activation, as judged by degradation of fodrin, occurred only in the ipsilateral hemisphere. In this study we demonstrate that calpastatin, the specific, endogenous inhibitor protein to calpain, is up-regulated in response to hypoxia and may be responsible for the halted calpain activation in the contralateral hemisphere. Concomitantly, extensive degradation of calpastatin occurred in the ipsilateral hemisphere, as demonstrated by the appearance of a membrane-bound 50-kDa calpastatin breakdown product. The calpastatin breakdown product accumulated in the synaptosomal fraction, displaying a peak 24 h post-insult, but was not detectable in the cytosolic fraction. The degradation of calpastatin was blocked by administration of CX295, a calpain inhibitor, indicating that calpastatin acts as a suicide substrate to calpain during hypoxia-ischemia. In summary, calpastatin was up-regulated in areas that remain undamaged and degraded in areas where excessive activation of calpains and infarction occurs. 相似文献
85.
Per Nilsson Nobuhisa Iwata Shin‐ichi Muramatsu Lars O. Tjernberg Bengt Winblad Takaomi C. Saido 《Journal of cellular and molecular medicine》2010,14(4):741-757
- ? Introduction
- ? Targets and ongoing research
- ‐ NGF
- ‐ Neurotrophic function of NGF
- ‐ Levels of NGF in AD
- ‐ Role of NGF in AD
- ‐ NGF as a therapeutic agent
- ‐ Development of NGF gene therapy
- ‐ In vivo gene delivery of NGF
- ‐ BDNF
- ‐ Neurotrophic function of BDNF
- ‐ BDNF levels in AD
- ‐ BDNF function in AD
- ? Towards BDNF gene therapy
- ‐ Neprilysin
- ‐ Role of neprilysin in AD
- ‐ Neprilysin levels in AD
- ‐ Gene delivery of neprilysin in AD animal models
- ‐ NGF
- ? Potential gene therapy target candidates
- ‐ APOE
- ‐ ECE
- ‐ Cathepsin B
- ‐ Other Aβ degrading enzymes
- ? Down‐regulation of AD‐associated proteins by siRNA
- ‐ BACE1
- ‐ APP
- ? Concluding remarks
86.
Hong Zhao Jinmin Zhu Kemi Cui Xiaoyin Xu Megan O'Brien Kelvin K Wong Santosh Kesari Weiming Xia Stephen TC Wong 《Cancer cell international》2009,9(1):15
Background
Cancer and Alzheimer's disease (AD) are two seemingly distinct diseases and rarely occur simultaneously in patients. To explore molecular determinants differentiating pathogenic routes towards AD or cancer, we investigate the role of amyloid β protein (Aβ) on multiple tumor cell lines that are stably expressing luciferase (human glioblastoma U87; human breast adenocarcinoma MDA-MB231; and mouse melanoma B16F). 相似文献87.
Neprilysin-sensitive synapse-associated amyloid-beta peptide oligomers impair neuronal plasticity and cognitive function 总被引:2,自引:0,他引:2
Huang SM Mouri A Kokubo H Nakajima R Suemoto T Higuchi M Staufenbiel M Noda Y Yamaguchi H Nabeshima T Saido TC Iwata N 《The Journal of biological chemistry》2006,281(26):17941-17951
A subtle but chronic alteration in metabolic balance between amyloid-beta peptide (Abeta) anabolic and catabolic activities is thought to cause Abeta accumulation, leading to a decade-long pathological cascade of Alzheimer disease. However, it is still unclear whether a reduction of the catabolic activity of Abeta in the brain causes neuronal dysfunction in vivo. In the present study, to clarify a possible connection between a reduction in neprilysin activity and impairment of synaptic and cognitive functions, we cross-bred amyloid precursor protein (APP) transgenic mice (APP23) with neprilysin-deficient mice and biochemically and immunoelectron-microscopically analyzed Abeta accumulation in the brain. We also examined hippocampal synaptic plasticity using an in vivo recording technique and cognitive function using a battery of learning and memory behavior tests, including Y-maze, novel-object recognition, Morris water maze, and contextual fear conditioning tests at the age of 13-16 weeks. We present direct experimental evidence that reduced activity of neprilysin, the major Abeta-degrading enzyme, in the brain elevates oligomeric forms of Abeta at the synapses and leads to impaired hippocampal synaptic plasticity and cognitive function before the appearance of amyloid plaque load. Thus, reduced neprilysin activity appears to be a causative event that is at least partly responsible for the memory-associated symptoms of Alzheimer disease. This supports the idea that a strategy to reduce Abeta oligomers in the brain by up-regulating neprilysin activity would contribute to alleviation of these symptoms. 相似文献
88.
Nakagawa K Kitazume S Oka R Maruyama K Saido TC Sato Y Endo T Hashimoto Y 《Journal of neurochemistry》2006,96(4):924-933
Alzheimer's disease (AD) is characterized by amyloid-beta peptide (Abeta) deposition in the brain. Abeta is produced by sequential cleavage of amyloid precursor protein (APP) by beta-secretase (BACE1: beta-site APP-cleaving enzyme 1) and gamma-secretase. Previously, we demonstrated that BACE1 also cleaves beta-galactoside alpha2,6-sialyltransferase (ST6Gal-I) and down-regulates its transferase activity. Here, we report that overexpression of ST6Gal-I in Neuro2a cells enhanced alpha2,6-sialylation of endogenous APP and increased the extracellular levels of its metabolites [Abeta by two-fold, soluble APPbeta (sAPPbeta) by three-fold and sAPPalpha by 2.5-fold). Sialylation-deficient mutant (Lec-2) cells secreted half as much Abeta as wild-type Chinese hamster ovary (CHO) cells. Furthermore, wild-type CHO cells showed enhanced secretion of the APP metabolites upon ST6Gal-I overexpression, whereas Lec-2 cells did not, indicating that the secretion enhancement requires sialylation of cellular protein(s). Secretion of metabolites from a mutant APP (APP-Asn467,496Ala) that lacked N-glycosylation sites was not enhanced upon ST6Gal-I overexpression, suggesting that the N-glycans on APP itself are required for the enhanced secretion. In the mouse brain, the amount of alpha2,6-sialylated APP appeared to be correlated with the sAPPbeta level. These results suggest that sialylation of APP promotes its metabolic turnover and could affect the pathology of AD. 相似文献
89.
90.
Yahata N Asai M Kitaoka S Takahashi K Asaka I Hioki H Kaneko T Maruyama K Saido TC Nakahata T Asada T Yamanaka S Iwata N Inoue H 《PloS one》2011,6(9):e25788