• BMB Reports
• /
• 제43권10호
• /
• pp.656-663
• /
• 2010

Amyloid precursor protein (APP), which is critically involved in the pathogenesis of Alzheimer's disease (AD), is cleaved by gamma/epsilon-secretase activity and results in the generation of different lengths of the APP Intracellular C-terminal Domain (AICD). In spite of its small size and short half-life, AICD has become the focus of studies on AD pathogenesis. Recently, it was demonstrated that AICD binds to different intracellular binding partners ('adaptor protein'), which regulate its stability and cellular localization. In terms of choice of adaptor protein, phosphorylation seems to play an important role. AICD and its various adaptor proteins are thought to take part in various cellular events, including regulation of gene transcription, apoptosis, calcium signaling, growth factor, and $NF-{\kappa}B$ pathway activation, as well as the production, trafficking, and processing of APP, and the modulation of cytoskeletal dynamics. This review discusses the possible roles of AICD in the pathogenesis of neurodegenerative diseases including AD.

• The Korean Journal of Physiology and Pharmacology
• /
• 제14권4호
• /
• pp.229-233
• /
• 2010

Amyloid precursor protein binding protein-1 (APP-BP1) binds to the carboxyl terminus of amyloid precursor protein and serves as a bipartite activation enzyme for the ubiquitin-like protein, NEDD8. Previously, it has been reported that APP-BP1 rescues the cell cycle S-M checkpoint defect in Ts41 hamster cells, that this rescue is dependent on the interaction of APP-BP1 with hUba3. The exogenous expression of APP-BP1 in neurons has been reported to cause DNA synthesis and apoptosis via a signaling pathway that is dependent on APP-BP1 binding to APP. These results suggest that APP-BP1 overexpression contributes to neurodegeneration. In the present study, we explored whether APP-BP1 expression was altered in the brains of Tg2576 mice, which is an animal model of Alzheimer's disease. APP-BP1 was found to be up-regulated in the hippocampus and cortex of 12 month-old Tg2576 mice compared to age-matched wild-type mice. In addition, APP-BP1 knockdown by siRNA treatment reduced cullin-1 neddylation in fetal neural stem cells, suggesting that APP-BP1 plays a role in cell cycle progression in the cells. Collectively, these results suggest that increased expression of APP-BP1, which has a role in cell cycle progression in neuronal cells, contributes to the pathogenesis of Alzheimer's disease.

• 동의신경정신과학회지
• /
• 제21권2호
• /
• pp.191-200
• /
• 2010

Objectives : This experiment was designed to investigate the effect of Chongmyung-Tang Prescription Combination(CmTP-$C_{1-10}$) extract on the production of amyloid $\beta$ protein and $\beta$-site amyloid precursor protein-cleaving enzyme(BACE) activity. Methods : The effect of CmTP-$C_{1-10}$ extract on expression of APP mRNA, BACE2 mRNA in BV2 microglia cell line treated by lipopolysacchride(LPS) and amyloid $\beta$ protein fragment(A$\beta$ fragment) were investigated. The effect of CmTP-$C_{1-10}$ extract on production of amyloid $\beta$ protein(A$\beta$) in BV2 microglia cell line treated by LPS and A$\beta$ fragment were investigated. The effect of CmTP-$C_{1-10}$ extract on BACE activity were investigated. Results : 1. CmTP-$C_9$ extract the most significantly suppressed the expression of APP mRNA, BACE2 mRNA in BV2 microglia cell line treated by LPS and A$\beta$ fragment. 2. CmTP-$C_9$ extract significantly suppressed the production of A$\beta$ in BV2 microglia cell line treated by LPS and A$\beta$ fragment. 3. CmTP-$C_9$ extract the most significantly inhibited BACE activity. Conclusions : These results suggest that CmTP-$C_9$ may be effective for the prevention and treatment of Alzheimer's Disease. Investigation into clinical use of CmTP-$C_9$ for Alzheimer's Disease is suggested for future research.

• Biomolecules & Therapeutics
• /
• 제27권3호
• /
• pp.276-282
• /
• 2019

${\beta}$-amyloid precursor protein (APP) can be cleaved by ${\alpha}$-, and ${\gamma}$-secretase at plasma membrane producing soluble ectodomain fragment ($sAPP{\alpha}$). Alternatively, following endocytosis, APP is cleaved by ${\beta}$-, and ${\gamma}$-secretase at early endosomes generating ${\beta}$-amyloid ($A{\beta}$), the main culprit in Alzheimer's disease (AD). Thus, APP endocytosis is critical for $A{\beta}$ production. Recently, we reported that Monsonia angustifolia, the indigenous vegetables consumed in Tanzania, improved cognitive function and decreased $A{\beta}$ production. In this study, we examined the underlying mechanism of justicidin A, the active compound of M. angustifolia, on $A{\beta}$ production. We found that justicidin A reduced endocytosis of APP, increasing $sAPP{\alpha}$ level, while decreasing $A{\beta}$ level in HeLa cells overexpressing human APP with the Swedish mutation. The effect of justicidin A on $A{\beta}$ production was blocked by endocytosis inhibitors, indicating that the decreased APP endocytosis by justicidin A is the underlying mechanism. Thus, justicidin A, the active compound of M. angustifolia, may be a novel agent for AD treatment.

• BMB Reports
• /
• 제49권6호
• /
• pp.337-343
• /
• 2016

Understanding of trafficking, processing, and degradation mechanisms of amyloid precursor protein (APP) is important because APP can be processed to produce β-amyloid (Aβ), a key pathogenic molecule in Alzheimer's disease (AD). Here, we found that APP contains KFERQ motif at its C-terminus, a consensus sequence for chaperone-mediated autophagy (CMA) or microautophagy which are another types of autophagy for degradation of pathogenic molecules in neurodegenerative diseases. Deletion of KFERQ in APP increased C-terminal fragments (CTFs) and secreted N-terminal fragments of APP and kept it away from lysosomes. KFERQ deletion did not abolish the interaction of APP or its cleaved products with heat shock cognate protein 70 (Hsc70), a protein necessary for CMA or microautophagy. These findings suggest that KFERQ motif is important for normal processing and degradation of APP to preclude the accumulation of APP-CTFs although it may not be important for CMA or microautophagy.

• 식품보건융합연구
• /
• 제4권4호
• /
• pp.18-25
• /
• 2018

Proteins play a key role in many functions such as metabolic activity, differentiation, as cargos and cell fate regulators. It is necessary to know about the markers involved in male fertility in order to develop remedies for the treatment of male infertility. But, the role of the proteins is not limited to particular function in the biological systems. Some of the proteins act as ion channels such as catsper and proteins like Nanos acts as a translational repressor in germ cells and expressed in prenatal period whose role in male fertility is uncertain. Rbm5 is a pre mRNA splicing factor necessary for sperm differentiation whose loss of function results deficit in sperm production. DEFB114 is a beta defensin family protein necessary for sperm motility in LPS challenged mice where as TEX 101 is a plasma membrane specific germ cell protein whose function is not clearly known u to now. Gpr56 is another adhesion protein whose null mutation leads to arrest of production of pups in rats. Amyloid precursor protein role in Alzheimer's disease is already known but it plays an important role in male fertility also but its function is uncertain and has to be considered while targeting APP during the treatment of Alzheimer's disease. The study on amyloid precursor protein in male fertility is a novel thing but requires further study in correlation to alzheimer's disease.

• Toxicological Research
• /
• 제29권4호
• /
• pp.235-240
• /
• 2013

Extracellular accumulation of amyloid beta protein ($A{\beta}$) plays a central role in Alzheimer's disease (AD). Some metals, such as copper, lead, and aluminum can affect the $A{\beta}$ accumulation in the brain. However, the effect of mercury on $A{\beta}$ accumulation in the brain is not clear. Thus, this study was proposed to estimate whether mercury concentration affects $A{\beta}$ accumulation in PC12 cells. We treated 10, 100, and 1000 nM $HgCl_2$ (Hg) or $CH_3HgCl_2$ (MeHg) for 48 hr in PC12 cells. After treatment, $A{\beta}_{40}$ in culture medium increased in a dose- and time-dependent manner. Hg and MeHg increased amyloid precursor protein (APP), which is related to $A{\beta}$ production. Neprilysin (NEP) levels in PC12 cells were decreased by Hg and MeHg treatment. These results suggested that Hg induced $A{\beta}$ accumulation through APP overproduction and reduction of NEP.

• Biomolecules & Therapeutics
• /
• 제29권3호
• /
• pp.290-294
• /
• 2021

Extracellular beta amyloid (Aβ) plaques are the neuropathological hallmarks of Alzheimer's disease (AD). Accordingly, reducing Aβ levels is considered a promising strategy for AD prevention. 3'-O-acetyl-24-epi-7,8-didehydrocimigenol-3-O-β-D-xylopryranoside significantly decreased the Aβ production and this effect was accompanied with reduced sAPPβ production known as a soluble ectodomain APP fragment through β-secretases in HeLa cells overexpressing amyloid precursor proteins (APPs). This compound also increased the level of sAPPα, which is a proteolytic fragment of APP by α-secretases. In addition, 3'-O-acetyl-24-epi-7,8-didehydrocimigenol-3-O-β-D-xylopryranoside decreased the protein level of β-secretases, but the protein levels of A disintegrin and metalloproteinase (ADAM) family, especially ADAM10 and ADAM17, are increased. Thus, 3'-O-acetyl-24-epi-7,8-didehydrocimigenol-3-O-β-D-xylopryranoside could be useful in the development of AD treatment in the aspect of amyloid pathology.

• Journal of Microbiology
• /
• 제44권6호
• /
• pp.665-670
• /
• 2006

Amyloid $\beta$-peptide (A$\beta$), which is a product of the proteolytic effect of $\beta$-secretase (BACE) on an amyloid precursor protein, is closely associated with Alzheimer's disease (AD) pathogenesis. There is sufficient evidence to suggest that a BACE inhibitor may reduce A$\beta$ levels, thus decreasing the risk of AD. In a previous study, an extract of Clavicorona pyxidata DGUM 29005 mycelia was found to inhibit the production of a soluble $\beta$-amyloid precursor protein (s$\beta$APP), A$\beta$, and BACE in neuronal cell lines. We sought to determine whether this mycelial extract exerts the same effect in human rhabdomyosarcoma A-204 and rat pheochromocytoma PC-12 cells. We found that the production of A$\beta$ decreased in a dose-dependent manner in the presence of the mycelial extract and that the concentration of A$\beta$ never exceeded $50{\mu}g/ml$. The presence of sAPP was detected in every culture medium to which the mycelial extract had been added and its concentration remained the same, regardless of the concentration of the extract used. Endogenous $\beta$-secretase activity in A-204 and PC-12 cellular homogenates also decreased in the presence of this extract. These cells, in culture, were not susceptible to the cytotoxic activity of the mycelial extract.

• The Korean Journal of Physiology and Pharmacology
• /
• 제13권3호
• /
• pp.195-200
• /
• 2009

Zinc released from excited glutamatergic neurons accelerates amyloid ${\beta}$ (A ${\beta}$) aggregation, underscoring the therapeutic potential of zinc chelation for the treatment of Alzheimer's disease (AD). Zinc can also alter A ${\beta}$ concentration by affecting its degradation. In order to elucidate the possible role of zinc influx in secretase-processed A ${\beta}$ production, SH-SY5Y cells stably expressing amyloid precursor protein (APP) were treated with pyrrolidine dithiocarbamate (PDTC), a zinc ionophore, and the resultant changes in APP processing were examined. PDTC decreased A ${\beta}$ 40 and A ${\beta}$ 42 concentrations in culture media bathing APP-expressing SH-SY5Y cells. Measuring the levels of a series of C-terminal APP fragments generated by enzymatic cutting at different APP-cleavage sites showed that both ${\beta}$-and ${\alpha}$-cleavage of APP were inhibited by zinc influx. PDTC also interfered with the maturation of APP. PDTC, however, paradoxically increased the intracellular levels of A ${\beta}$ 40. These results indicate that inhibition of secretase-mediated APP cleavage accounts -at least in part- for zinc inhibition of A ${\beta}$ secretion.