• Bulletin of the Korean Chemical Society
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• 제34권5호
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• pp.1503-1507
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• 2013

The two major symptoms characterizing Alzheimer's disease are the formation of amyloid-${\beta}$ extracellular deposits in the form of senile plaques and intracellular neurofibrillary tangles (NFTs) that consist of pathological hyperphosphorylated tau protein aggregated into insoluble paired helical filaments (PHFs). Neurons of the central nervous system have appreciable amounts of tau protein, a microtubule-associated protein. To maintain an optimal operation of nerves, the microtubules are stabilized, which is necessary to support cell structure and cellular processes. When the modified tau protein becomes dysfunctional, the cells containing misfolded tau cannot maintain cell structure. One of the pathological hallmarks of Alzheimer's disease is hyperphosphorylated tau protein. This paper shows that the small heat shock protein from humans (Hsp27) reduces hyperphosphorylated tau and prevents hyperphosphorylated tau-induced cell death of the human neuroblastoma cell line SH-SY5Y.

• 대한치매학회지
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• 제23권4호
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• pp.188-201
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• 2024

Alzheimer's disease (AD), a leading cause of dementia, presents a formidable global health challenge intensified by the aging population. This review encapsulates the evolving landscape of AD diagnosis and treatment with a special focus on the innovative role of fluid biomarkers. Pathologically, AD is marked by amyloid beta (Aβ) plaques and neurofibrillary tangles of hyperphosphorylated tau, which lead to synaptic dysfunction, neuronal loss, and cognitive decline. These pathological changes, commencing decades before symptom onset, underscore the need for early detection and intervention. Diagnosis traditionally relies on clinical assessment, neuropsychological testing, and neuroimaging techniques. However, fluid biomarkers in cerebrospinal fluid and blood, such as various forms of Aβ, total tau, phosphorylated tau, and neurofilament light chain, are emerging as less invasive, cost-effective diagnostic tools. These biomarkers are pivotal for early diagnosis, differential diagnosis, disease progression monitoring, and treatment response evaluation. The treatment landscape is shifting toward personalized medicine, highlighted by advancements in Aβ immunotherapies, such as lecanemab and donanemab. Demonstrating efficacy in phase III clinical trials, these therapies hold promise as tailored treatment strategies based on individual biomarker profiles. The integration of fluid biomarkers into clinical practice represents a significant advance in AD management, providing the potential for early and precise diagnosis, coupled with personalized therapeutic approaches. This heralds a new era in combating this debilitating disease.

• 운동영양학회지
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• 제16권2호
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• pp.93-100
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• 2012

Alzheimer's disease (AD) is the most common cause of dementia in adults. Microtubule associated protein tau is abnormally phosphorylated in AD and aggregates as paired helical filaments (PHFs) in neurofibrillary tangles (NFTs). NFTs are the most common intraneuronal inclusion in the brains of patients with AD and have been implicated in mediating neuronal cell death and cognitive deficit. Aberrant phosphorylation of tau is an early pathological event in AD, but the underlying mechanisms are unclear. MAP kinases are a family of Serine/Threonine (Ser/Thr) kinases that involved hyper - phosphorylation of tau in AD. The purpose of this study was to investigate the effect of treadmill exercise on phosphorylation of tau level and activation of MAPKs including JNK, ERK, p38-MAPK. To address this, Tg mouse model of AD, Tg-NSE/hTau 23, which expresses human tau 23 in the brain, was chosen. Animals were subjected to treadmill exercise for 12 weeks from 24 months of age. Treadmill exercise in Tg group improved cognitive function compared with Tg-SED group in watermaze test. In addition, treadmill exercised Tg mice significantly reduced the activation of JNK54/46, p38-MAPK and tau (Ser404, Ser202, Thr231), and increased activation of ERK44/42 in cerebral cortex. These results suggest that treadmill exercise may provide a therapeutic potential to alleviate the tau pathology like AD.

• Natural Product Sciences
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• 제26권3호
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• pp.221-229
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• 2020

This study was undertaken to investigate the protective effect of rice bran oil (RBO) on amyloid β protein (Aβ) (25-35)-induced memory impairment and brain damage in an ICR mouse model. Memory impairment was produced by intracerebroventricular microinjection of 15 nmol Aβ (25-35) and assessed using the passive avoidance test. Treatment with RBO at 0.1, 0.5, or 1 mL/kg (p.o. daily for 8 days) protected against Aβ (25-35)-induced memory impairment. Furthermore, Aβ (25-35)-induced decreases in glutathione and increases in lipid peroxidation and cholinesterase activity in brain tissue were inhibited by RBO, and Aβ (25-35)-induced increases of phosphorylated mitogen-activated protein kinases (MAPKs) and inflammatory factors, and changes in the levels of apoptosis-related proteins were significantly inhibited by RBO. Furthermore, Aβ (25-35) suppressed the PI3K/Akt pathway and the phosphorylation of CREB, but increased phosphorylation of tau (p-tau) in mice brain; these effects were significantly inhibited by administration of RBO. These results suggest that RBO inhibits Aβ (25-35)-induced memory impairment by inducing anti-apoptotic and anti-inflammatory effects, promoting PI3K/Akt/CREB signaling, and thus, inhibiting p-tau formation.

• 생물정신의학
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• 제8권1호
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• pp.62-70
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• 2001

Alzheimer's disease(AD) is associated with a characteristic neuropathology. The major hallmarks of AD are senile plaques (SPs) and neurofibrillary tangles(NFTs). ${\beta}$-amyloid protein($A{\beta}$) is derived from the proteolysis of amyloid precursor protein(APP) and then converted to SPs. Mature SPs produce cytotoxicity through direct toxic effects and activation of microglia and complement. NFTs are composed of paired helical filaments(PHFs) including abnormally phosphorylated form of the microtubule-associated protein(MAP) tau and increased tau level in cerebrospinal fluid may be observed in most AD. The aggregation of $A{\beta}$ and tau formation are thought to be a final common pathway of AD. Acetylcholine, dopamine, serotonin, GABA and their receptors are associated with AD. Especially, decreased nicotinic acetylcholine receptors(nAChRs) in AD are reported. Genetic lesions associated with AD are mutations in the structural genes for the APP located on chromosome 21, presenilin(PSN)1 located on chromosome 14 and PSN2 located on chromosome 1. Also, trisomy 21, Apo-E gene located on chromosome 19, PMF locus, low density lipoprotein receptor-related protein and ${\alpha}$-macroglobulin increase risk of AD. In this article, we will review about the neurobiology of AD and some newly developed research areas.

• 대한임상검사과학회지
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• 제54권4호
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• pp.249-255
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• 2022

알츠하이머병은 주요한 공중보건 문제로 나타나며 연구분야에서도 최우선적인 과제이다. 알츠하이머병(AD)에서 뇌척수액(CSF)을 활용한 바이오마커인 아밀로이드-β(Aβ42), 총 타우(T-tau) 및 인산화 타우(P-tau)가 알츠하이머병 병태생리학의 핵심 요소를 반영한다. 임상 연구 및 새로운 측정법을 통한 임상적으로 활용되는 진단은 전임상 알츠하이머병에 대해 민감적이고 특이적이며 신뢰할 수 있는 바이오마커의 발굴, 뿐만 아니라 치매의 조기 발견 및 감별 진단과 질병 진행 모니터링에 도움이 되는 검사법의 개발에도 중요할 것이다. 증상 전 단계에서 AD의 조기 발견은 시냅스 손상 및 신경 손실이 확장되기 전에 개입이 수행되기 때문에 치료 개입을 조기에 가능하게 하고 치료 성공을 위한 가능성이 더 큰 좋은 기회로 이어진다. 따라서 새롭고 접근하기 쉽고 비용이 적게 드는 바이오마커를 임상 진단에 활용하는 것이 매우 유익할 것이다. 치매의 초기단계에 일어나는 병리학적 변화나, 질병의 진행정도를 추적할 수 있는 다양한 바이오마커들의 진단방법을 찾는 일은 치료제 개발처럼 중요한 연구 분야이다. 조기진단을 위해 임상증상을 대변하거나(surrogate marker), 증상이 나타나기 이전 상태를 측정할 수 있는 새로운 진단마커가 필요한 상황이다. 이러한 이유로 인지기능 저하정도를 측정하여 정상, 경도인지장애(mild cognition impairment, MCI) 및 전임상(preclinical) 상태의 사람을 판별할 수 있는 바이오마커(biomarker)를 활용한 조기진단법 개발의 중요성이 강조되고 있다.

• Journal of Ginseng Research
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• 제45권6호
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• pp.665-675
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• 2021

Background: Ginsenoside Rg1 (Rg1), an active ingredient in ginseng, may be a potential agent for the treatment of Alzheimer's disease (AD). However, the protective effect of Rg1 on neurodegeneration in AD and its mechanism of action are still incompletely understood. Methods: Wild type (WT) and APP/PS1 AD mice, from 6 to 9 months old, were used in the experiment. The open field test (OFT) and Morris water maze (MWM) were used to detect behavioral changes. Neuronal damage was assessed by hematoxylin and eosin (H&E) and Nissl staining. Immunofluorescence, western blotting, and quantitative real-time polymerase chain reaction (q-PCR) were used to examine postsynaptic density 95 (PSD95) expression, amyloid beta (Aβ) deposition, Tau and phosphorylated Tau (p-Tau) expression, reactive oxygen species (ROS) production, and NAPDH oxidase 2 (NOX2) expression. Results: Rg1 treatment for 12 weeks significantly ameliorated cognitive impairments and neuronal damage and decreased the p-Tau level, amyloid precursor protein (APP) expression, and Aβ generation in APP/PS1 mice. Meanwhile, Rg1 treatment significantly decreased the ROS level and NOX2 expression in the hippocampus and cortex of APP/PS1 mice. Conclusions: Rg1 alleviates cognitive impairments, neuronal damage, and reduce Aβ deposition by inhibiting NOX2 activation in APP/PS1 mice.

• 대한의생명과학회지
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• 제21권1호
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• pp.1-8
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• 2015

Alzheimer's disease is a common form of dementia occurring among the elderly population and can be identified by symptoms such as cognition impairments, memory loss and neuronal dysfunction. Alzheimer's disease was found to be caused by the deposition of $\beta$-amyloid plaques and neurofibrillary tangles. In addition, mutation in the APP (Amyloid precursor protein), Presenilin 1 (PSEN1) and Presenilin 2 (PSEN2) genes were also found to contribute to Alzheimer's disease. Since the potential conformational diagnosis of Alzheimer's disease requires histopathological tests on brain through autopsy, potential early diagnosis still remains challenging. In recent years, several researches have proposed the use of biomarkers for early diagnosis. In cerebrospinal fluid (CSF), $\beta$-amyloid(1-42), phosphorylated-tau and total tau were suggested to be effective biomarkers for Alzheimer's disease diagnosis. However, a single biomarker might not be sufficient for potential diagnosis of Alzheimer's disease. Thus, the use of RNA interference (RNAi) through microRNAs (miRNAs) has been proposed by several researchers for simultaneous analysis of several biomarkers using microarray technology. These miRNA based biomarkers can be analysed from both blood and CSF, but miRNAs from blood are advantageous over CSF as they are non-invasive and simple for collection. Moreover, the RNAi based therapeutics by siRNA (short interference RNA) or shRNA (short hairpin RNA) have also been proposed to be effective in the treatment of Alzheimer's disease. This review describes the promising application of RNAi technology in therapeutics and as a biomarker for both Alzheimer's disease diagnosis and treatment.

• The Korean Journal of Physiology and Pharmacology
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• 제24권4호
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• pp.299-310
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• 2020

Alzheimer's disease (AD) is a multi-faceted neurodegenerative disease. Thus, current therapeutic strategies require multitarget-drug combinations to treat or prevent the disease. At the present time, single drugs have proven to be inadequate in terms of addressing the multifactorial pathology of AD, and multitarget-directed drug design has not been successful. Based on these points of views, it is judged that combinatorial drug therapies that target several pathogenic factors may offer more attractive therapeutic options. Thus, we explored that the combination therapy with lower doses of cilostazol and aripiprazole with add-on donepezil (CAD) might have potential in the pathogenesis of AD. In the present study, we found the superior efficacies of donepezil add-on with combinatorial mixture of cilostazol plus aripiprazole in modulation of expression of AD-relevant genes: Aβ accumulation, GSK-3β, P300, acetylated tau, phosphorylated-tau levels, and activation of α-secretase/ADAM 10 through SIRT1 activation in the N2a Swe cells expressing human APP Swedish mutation (N2a Swe cells). We also assessed that CAD synergistically raised acetylcholine release and choline acetyltransferase (CHAT) expression that were declined by increased β-amyloid level in the activated N2a Swe cells. Consequently, CAD treatment synergistically increased neurite elongation and improved cell viability through activations of PI3K, BDNF, β-catenin and α7-nicotinic cholinergic receptors in neuronal cells in the presence of Aβ_1-42. This work endorses the possibility for efficient treatment of AD by supporting the synergistic therapeutic potential of donepezil add-on therapy in combination with lower doses of cilostazol and aripiprazole.

• 생약학회지
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• 제47권3호
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• pp.251-257
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• 2016

In this study, the radical scavenging activity and protective effect of ethanol extract from leaf of Engelhardtia chrysolepis HANCE (ECE) against oxidative stress were investigated under in vitro and cellular system. ECE showed strong radical scavenging activities in 1,1-diphenyl-2-picrylhydrazyl, hydroxyl(${\cdot}OH$) and nitric oxide(NO) radical as a concentration-dependent manner. Particularly, strong scavenging activity against the ${\cdot}OH$ and NO radical were observed with the $IC_{50}$ value of $1.30{\mu}g/ml$ and $12.61{\mu}g/ml$, respectively. Furthermore, the cellular oxidative stress was induced by amyloid beta($A{\beta}_{25-35}$) in C6 glial cells. The treatment of $A{\beta}_{25-35}$ to C6 glial cells generated high levels of reactive oxygen species(ROS) and declined cell viability. However, production of ROS was decreased by the treatment of ECE. In addition, the cell viability was significantly increased at each concentration(10, 25, $50{\mu}g/ml$) as dose-dependent manner. The Alzheimer's disease-related protein expressions in $A{\beta}_{25-35}$-treated C6 glial cells were analyzed. The ECE treatment inhibited expression of amyloid precursor protein(APP), C-terminal fragment-${\beta}(CTF-{\beta})$, ${\beta}$-site APP cleaving enzyme(BACE), phosphorylated tau(p-tau) proteins in C6 glial cells induced by $A{\beta}_{25-35}$. The present study indicated that ECE has strong radical scavenging activity and neuroprotective effect through attenuating oxidative stress.