• Fisheries and Aquatic Sciences
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• 제21권5호
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• pp.13.1-13.8
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• 2018

Amyloid plaque, also called senile plaque, the product of aggregation of ${\beta}$-amyloid peptides ($A{\beta}$), is observed in brains of the patients with Alzheimer's disease (AD) and is one of the key factors in etiology of the disease. In this study, hydrolysates obtained from the sea hare (Aplysia kurodai) were investigated for ${\beta}$-secretase inhibitory peptide. The sea hare's muscle protein was hydrolyzed using six enzymes in a batch reactor. Trypsin hydrolysate had highest ${\beta}$-secretase inhibitory activity compared to the other hydrolysates. ${\beta}$-secretase inhibitory peptide was separated using Sephadex G-25 column chromatography and high-performance liquid chromatography on a C18 column. ${\beta}$-secretase inhibitory peptide was identified as eight amino acid residues of Val-Ala-Ala-Leu-Met-Leu-Phe-Asn by N-terminal amino acid sequence analysis. $IC_{50}$ value of purified ${\beta}$-secretase inhibitory peptide was $74.25{\mu}M$, and Lineweaver-Burk plots suggested that the peptide purified from sea hare muscle protein acts as a competitive inhibitor against ${\beta}$-secretase. Results of this study suggest that peptides derived from sea hare muscle may be beneficial as anti-dementia compounds in functional foods or as pharmaceuticals.

• Molecules and Cells
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• 제40권9호
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• pp.613-620
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• 2017

The most common form of senile dementia is Alzheimer's disease (AD), which is characterized by the extracellular deposition of amyloid ${\beta}-peptide$ ($A{\beta}$) plaques and the intracellular formation of neurofibrillary tangles (NFTs) in the cerebral cortex. Tau abnormalities are commonly observed in many neurodegenerative diseases including AD, Parkinson's disease, and Pick's disease. Interestingly, tau-mediated formation of NFTs in AD brains shows better correlation with cognitive impairment than $A{\beta}$ plaque accumulation; pathological tau alone is sufficient to elicit frontotemporal dementia, but it does not cause AD. A growing amount of evidence suggests that soluble $A{\beta}$ oligomers in concert with hyperphosphorylated tau (pTau) serve as the major pathogenic drivers of neurodegeneration in AD. Increased $A{\beta}$ oligomers trigger neuronal dysfunction and network alternations in learning and memory circuitry prior to clinical onset of AD, leading to cognitive decline. Furthermore, accumulated damage to mitochondria in the course of aging, which is the best-known nongenetic risk factor for AD, may collaborate with soluble $A{\beta}$ and pTau to induce synapse loss and cognitive impairment in AD. In this review, I summarize and discuss the current knowledge of the molecular and cellular biology of AD and also the mechanisms that underlie $A{\beta}-mediated$ neurodegeneration.

• BMB Reports
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• 제49권7호
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• pp.376-381
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• 2016

Several lines of evidence have revealed that phosphorylation of amyloid precursor protein (APP) at Thr668 is involved in the pathogenesis of Alzheimer's disease (AD). Okadaic acid (OA), a protein phosphatase-2A inhibitor, has been used in AD research models to increase tau phosphorylation and induce neuronal death. We previously showed that OA increased levels of APP and induced accumulation of APP in axonal swellings. In this study, we found that in OA-treated neurons, phosphorylation of APP at Thr668 increased and accumulated in axonal swellings by c-jun N-terminal kinase (JNK), and not by Cdk5 or ERK/MAPK. These results suggest that JNK may be one of therapeutic targets for the treatment of AD.

• Molecular & Cellular Toxicology
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• 제5권2호
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• pp.108-112
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• 2009

Alzheimer's disease(AD) is a neurodegenerative disorder characterized pathologically by senile plaques, neurofibrillary tangles, and synapse loss. Especially, extracellular beta-amyloid (Abeta) deposition is a major pathological hallmark of Alzheimer's disease (AD). In AD senile plaques, high level of iron and car-bonylated Abeta were detected. Iron has a Lewis acid property which can increase the electrophilicity of carbonyls, which may react catalytically with nucleophiles, such as amines. Hence, this study investigated whether or not iron could promote the carbonylation of amine with malondialdehyde (MDA) in the physiological condition. As the basic study, we examined that iron might promote the conjugation reaction between propylamine, monoamine molecule and MDA in the physiological condition. As the concentration of iron increased, the fluorescence intensity produced from the conjugation reaction increased in a dose-dependent manner. Instead of propylamine, we applied the same reaction condition to Abeta 1-40 peptide, one of major components founded in AD senile plaques for the conjugation reaction. As the result, the fluorescence intensity produced from the conjugation reaction between Abeta 1-40 peptide and MDA showed the similar trend to that of the reaction used with propylamine. This study suggests that iron can accelerate the conjugation reaction of MDA to Abeta 1-40 peptide and play an another important role in deterioration of AD brain.

• 대한화학회지
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• 제58권6호
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• pp.553-559
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• 2014

Alzheimer's disease (AD) is a devastating neurodegenerative disease that represents the most common form of dementia among the elderly population. The deposition of aggregated ${\beta}$-amyloid ($A{\beta}$) senile plaques in the human brain is a classic observation in the neuropathology of AD, yet an understanding of the mechanism of their formation remains elusive. $A{\beta}$ is formed through endoproteolysis of the amyloid precursor protein (APP) by ${\beta}$-secretase (BACE1, ${\beta}$-site APP-cleaving enzyme) and ${\gamma}$-secretase. In this study, BACE1 protein was successfully over-expressed, purified, and refolded and utilized in a binding study with hispidin. We developed a simpler refolding method using a urea gradient and size-exclusion gel filtration to purify an active BACE1 protein variant, in larger quantities than that reported previously, and measured the binding affinity of hispidin to the BACE1 protein variant through isothermal titration calorimetry.

• Bulletin of the Korean Chemical Society
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• 제35권7호
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• pp.2065-2071
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• 2014

${\beta}$-Secretase (beta-amyloid converting enzyme 1 [BACE1]) is involved in the first and rate-limiting step of ${\beta}$-amyloid ($A{\beta}$) peptides production, which leads to the pathogenesis of Alzheimer's disease(AD). Therefore, inhibition of BACE1 activity has become an efficient approach for the treatment of AD. Ligand-based and docking-based 3D-quantitative structure-activity relationship (3D-QSAR) studies of acyl guanidine analogues were performed with comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) to obtain insights for designing novel potent BACE1 inhibitors. We obtained highly reliable and predictive CoMSIA models with a cross-validated $q^2$ value of 0.725 and a predictive coefficient $r{^2}_{pred}$ value of 0.956. CoMSIA contour maps showed the structural requirements for potent activity. 3D-QSAR analysis suggested that an acyl guanidine and an amide group in the $R_6$ substituent would be important moieties for potent activity. Moreover, the introduction of small hydrophobic groups in the phenyl ring and hydrogen bond donor groups in 3,5-dichlorophenyl ring could increase biological activity.

• Toxicological Research
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• 제27권1호
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• pp.19-23
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• 2011

It has been proposed that acute phase response can be a mechanism by which inhaled particles exert adverse effects on the cardiovascular system. Although some of the human acute phase proteins have been widely studied as biomarkers of systemic inflammation or cardiovascular diseases, there are only a few studies that investigated the role of serum amyloid P (SAP), a major acute phase protein in mice. In this study, we investigated the changes in SAP, following inhalation exposure to nickel hydroxide nanoparticles (nano-NH). We conducted 1) acute (4 h) exposure to nano-NH at 100, 500, and $1000\;{\mu}g/m^3$ and 2) sub-acute (4h/d for 3d) exposure at $1000\;{\mu}g/m^3$, then measured serum SAP protein levels along with hepatic Sap mRNA levels. The results show that inhaled nano-NH can induce systemic acute phase response indicated by increased serum SAP levels and hepatic Sap mRNA levels. To the best of our knowledge, this is the first study showing induction of SAP in response to repeated particle exposure, and the results suggest that SAP can be used as a biomarker for systemic inflammation induced by inhaled particles.

• 한국응용약물학회:학술대회논문집
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• 한국응용약물학회 2006년도 Spring Conference
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• pp.123-135
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• 2006

Alzheimer's disease (AD) is the most common form of dementia in the aging population and is clinically characterized by a progressive loss of cognitive abilities. Pathologically, it is defined by the appearance of senile plaques - extracellular insoluble, congophilic protein aggregates composed of amyloid $\beta$ (A$\beta$) and neurofibrillary tangles (NFTs) - inyracellular lesions consisting of paired helical filaments from hyperphosphorylated cytoskeletal tau protein as described by Alois Alzheimer a century ago. These hallmarks still serve as the major criteria for a definite diagnosis of the disease. Consequently, one of the key strategy for drug development in this disease area focuses on reducing the concentration of cerebral A$\beta$ plaque by using substances that inhibit A$\beta$ fibril formation. We focused on developing inhibitors by synthesizing several kinds of aromatic molecules. The synthetic compounds were initially screened to evaluate the effective compound by tioflavin T fluorescence assay. The selected effective compounds were tested cytotoxicity and protective effect from A$\beta$-induced neuronal toxicity by cell based MTT assay with HT22 hippocampal neurons. The BBB permeability on effectors was also tested in in vitro co-culture model(HUVEC/C6 cell line). The behavior test wea carried out in mutant APP/PS1 transgenic mouse model of Alzheimer's disease. And inhibition of A$\beta$ fibril formation by the effective compound was monitored with transmitted electron microscopic images.

• 한국응용약물학회:학술대회논문집
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• 한국응용약물학회 2006년도 Spring Conference
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• pp.77-90
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• 2006

Beta-amyloid peptide (A$\beta$) is a major component of senile plaques and its aggregation is considered to play a critical role in pathogenesis of Alzheimer's disease (AD). Aggregation of A$\beta$ could result from both increased synthesis and decreased degradation of A$\beta$. Our laboratory is interested in understanding the mechanism of A$\beta$ degradation in brain. Recently our laboratory identified a bacterial gene (SKAP) from Streptomyces sp KK565 whose protein product has an activity to cleave A$\beta$ and thus reduce the A$\beta$-induced neurotoxicity. The sequence analysis showed that this gene was closely related to aminopeptidase. Maldi-Tof analysis showed that the recombinant SKAP protein expressed in E. coli cleaves both A$\beta$ 40 and A$\beta$ 42 at the N-terminal of A$\beta$ while an aminopeptidase from Streptomyces griseus (SGAP) cleaves at the C-terminal. We also identified a mammalian homolog of SKAP and the recombinant mammalian protein expressed in Sf-9 insect cells showed a similar proteolytic activity to SGAP, cutting A$\beta$ at the C-terminus. I well discuss the detailed mechanism of the enzyme action and its functional implication in AD.

• Biomolecules & Therapeutics
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• 제19권2호
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• pp.181-186
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• 2011

Beta-amyloid (A${\beta}$) is considered as one of the major causes of Alzheimer's disease. This study examined the neuroprotective effects of chlorogenic acid, a naturally occurring polyphenol which is distributed widely in plants, fruits and vegetables, against A${\beta}$-induced toxicity. A${\beta}$ decreased significantly the viability of PC12 cells. This was accompanied by an increase in the intracellular calcium levels and cleaved caspase-3. In addition, A${\beta}$ induced an increase in Bax, and a decrease in Bcl-2 compared to the controls. However, a pre-treatment with chlorogenic acid rescued the PC12 cells from A${\beta}$ by attenuating the elevated intracellular calcium levels and reducing the levels of the apoptosis related proteins, including caspase-3, Bcl-2 and Bax. These results suggest that the protective effects of chlorogenic acid are, at least in parts, by attenuating the intracellular calcium influx and reducing apoptosis induced by A${\beta}$.