The Role of O-GlcNAcylation in Alzheimer’s Disease Pathogenesis

묵인희 한국당과학회 2021 한국당과학회 학술대회 Vol.2021 No.01

Since conventional secretory pathway from ER to Golgi is involved in many essential functions of a cell, it is an important to understand how transport vesicles are regulated. The pathway is initiated by ER’s making transport vesicles at ER exit sites (ERES) with specific coat protein complexes such as COPII vesicles. Our previous study showed that O-GlcNAcylation (O-GlcNAc) on Sec31A, a main component for COPII vesicle, accelerates the anterograde transport of vesicles in ER-Golgi networks. In the present study, we focused on the effect of Ab, a crucial factor in the pathogenesis of Alzheimer’s disease (AD), on the formation of COPII vesicles at ERES. Ab-induced disrupted intracellular calcium levels affected the formation of COPII vesicles at ERES through O-GlcNAcylation of Sec31A in neuronal cells. In addition, Ab caused Golgi fragmentation which was rescued by up-regulation of O-GlcNAcylation using Thiamet G, an OGA inhibitor. Overall, Ab impaired ERES formation through altered Sec31A O-GlcNAcylation triggered by disruption of intracellular calcium homeostasis, suggesting that protection of ERES or Sec31 O-GlcNAcylation may be a promising novel avenue for the development of AD therapeutics.

뇌와 마음-(6) 퇴행성 뇌질환의 병인과 치료전략-인생의 후반전, 적극적인 선수로 산다

묵인희 한국과학기술단체총연합회 2008 과학과 기술 Vol.41 No.11

Mechanism studies of secretases in Alzheimer's disease animal model

In-Hee Mook(묵인희) 한국실험동물학회 2004 한국실험동물학회 학술발표대회 논문집 Vol.2004 No.-

Diverse Molecular Targets for Therapeutic Strategies in Alzheimer’s Disease

한선호,묵인희 대한의학회 2014 Journal of Korean medical science Vol.29 No.7

Alzheimer’s disease (AD) is the most common form of dementia caused byneurodegenerative process and is tightly related to amyloid β (Aβ) and neurofibrillarytangles. The lack of early diagnostic biomarker and therapeutic remedy hinders theprevention of increasing population of AD patients every year. In spite of accumulatedscientific information, numerous clinical trials for candidate drug targets have failed to bepreceded into therapeutic development, therefore, AD-related sufferers including patientsand caregivers, are desperate to seek the solution. Also, effective AD intervention isdesperately needed to reduce AD-related societal threats to public health. In this review,we summarize various drug targets and strategies in recent preclinical studies and clinicaltrials for AD therapy: Allopathic treatment, immunotherapy, Aβ production/aggregationmodulator, tau-targeting therapy and metabolic targeting. Some has already failed in theirclinical trials and the others are still in various stages of investigations, both of which giveus valuable information for future research in AD therapeutic development.

The role of mitochondrial DNA mutation on neurodegenerative diseases

차문영,묵인희,김동규 생화학분자생물학회 2015 Experimental and molecular medicine Vol.47 No.-

Many researchers have reported that oxidative damage to mitochondrial DNA (mtDNA) is increased in several age-related disorders. Damage to mitochondrial constituents and mtDNA can generate additional mitochondrial dysfunction that may result in greater reactive oxygen species production, triggering a circular chain of events. However, the mechanisms underlying this vicious cycle have yet to be fully investigated. In this review, we summarize the relationship of oxidative stress-induced mitochondrial dysfunction with mtDNA mutation in neurodegenerative disorders.

베타-아밀로이드에 의한 신경세포 손상에 대한 제니스테인의 신경보호효과

방오영,묵인희,허균 대한신경과학회 2003 대한신경과학회지 Vol.21 No.2

Special issue on neurodegenerative diseases and their therapeutic approaches

김정수,묵인희 생화학분자생물학회 2015 Experimental and molecular medicine Vol.47 No.-

허혈성 신경세포손상이 아밀로이드 전구단백질의 대사에 미치는 영향

이필휴,황은미,묵인희,허균,최일생 대한신경과학회 2005 대한신경과학회지 Vol.23 No.2

Background: In spite of the different pathogenesis and exclusive respect in the diagnosis of Alzheimer's disease (AD) and vascular dementia (VaD), recent epidemiological and pathological studies indicates that ischemic stroke have an important role in the pathogenesis of both VaD and AD. However,the association of ischemic stroke and AD on the cellular and molecular level is still unknown. We evaluated the effect of ischemic neuronal insult on the regulation of amyloid precursor protein (APP) processing. Methods: We used an in vitro model of cerebral ischemia (oxygen-glucose deprivation, OGD) to evaluate the effect of ischemic insult on the amyloidogenic and non-amyloidogenic pathways using human neuroblastoma cell line, SH-SY5Y, and primary cultured cells of Tg2576 APP transgenic mouse. Results: Ischemic insult significantly increased the beta amyloid (Aβ) production in the primary cultured cells of Tg2576 APP transgenic mice (p<0.001). A disintegrin and metalloprotease 10 (ADAM 10), a candidate of α- secretase, was markedly increased in the early stage of ischemic insult (up to 2 hours of OGD, p<0.001; 4 hours of OGD, p<0.05), which was followed by the decreased level of ADAM 10 expression in a later stage (p<0.001). However, the protein and mRNA expression of β-site cleavage enzyme (BACE) and BACE activity were not significantly different between the group of ischemic insult and control. By contrast, the activity of γ-secretase was significantly increased after 4 hours of ischemic insult, as compared to controls. Conclusions: This study demonstrates that the ischemic neuronal insults increase the production of Aβ via activation of the amyloidogenic pathway, which may link the role of ischemic insults to the pathogenesis of AD.

Intracellular Aβ alter the tight junction of retinal pigment epithelium in 5XFAD mice

박성욱,김진형,묵인희,김규원,박규형,박우진,김정훈 한국실험동물학회 2013 한국실험동물학회 학술발표대회 논문집 Vol.2013 No.8

베타 아밀로이드 형성에 관여하는 효소와 그를 응용한 알츠하이머병 치료법 개발 동향

장창환,정민환,묵인희 한국뇌학회 2001 한국뇌학회지 Vol.1 No.1

알츠하이머병(Alzheimer's disease: AD)은 퇴행성 신경질환으로서 80세 이상 노인의 50% 정도가 고통을 받고 있는 병이다. 그 증상으로는 기억력 및 인지기능의 상실이 서서히 진행되어 나타나며 아직 정확한 병인이나 치료법은 알려지지 않고 있는 실정이다. AD의 병리학적 특징으로는 노인반점(senile plaques), 신경섬유덩어리(neurofibrilary tangles), 그리고 신경세포의 손실(neuronal loss)을 대표적으로 들 수 있다 하겠다. 노인반점의 대부분을 차지하고 있는 응집된 베타아밀로이드 단백질은 여러 가지 실험적 증거들에 의하여 AD의 주요 병인으로 생각되어지고 있다. AD는 크게 젊은 나이에 발병하는 유전성 AD(familial AD)와 원인을 알 수 없는 산발성 AD(sporadic AD)로 나눌 수 있다. 유전성 AD의 경우는 presenilin 1(PS1), presenilin 2(PS2) 혹은 아밀로이드 전구단백질(amyloid precursor protein, APP) 유전인자에 돌연변이가 일어났을 경우 100% AD로 발병하게 된다. 산발성 AD의 경우는 아포지단백질 E(apolipoprotein E)나 α-2 macroglobulin에 돌연변이가 일어났을 때 AD로 진전할 확률이 높아지는 위험인자는 밝혀져 있으나 발병의 정확한 원인은 알려진 것이 없다. 특이한 사항은 산발성이나 유전성 AD 모두 베타아밀로이드 단백질의 과다 침착이 공통적으로 일어난다는 것으로 베타아밀로이드의 AD의 병인으로서의 가능성을 시사하고 있다. 본 논문에서는 베타아밀로이드가 형성되어지는 대사경로를 설명하고 그 중 베타아밀로이드 생성에 관여하는 β-, γ-secretases에 관하여 최근의 연구결과들을 중점적으로 설명할 것이다. 또한 베타아밀로이드의 생성을 저해하는 α-secretase의 후보물질들에 관한 설명과 이러한 secretases들의 조절 및 이를 이용한 치매치료법에 관한 최근 동향을 설명하고자 한다. Alzheimer's disease (AD) is one of the most common senile dementia in elderly population. It is an age-related neurodegenerative disorder. Almost 50% of over 80 years old individuals suffer the problems with AD. Memory deficit which is resulted from degenerated neurons followed by synaptic loss is the major symptom of AD. The pathological hallmarks of AD are (1) extracellular deposit of senile plaques, (2) intracellular neurofibrillary tangles and (3) severe neuronal loss in the brain. Senile plaques consist of a central core of insoluble fibrillary amyloid β-protein (Aβ) surrounded by a halo of dystrophic neurites. Most of AD is sporadic form and less than 10% in AD is familial form. The mutations on the gene of amyloid precursor protein (APP), presenilin 1 (PS1) and presenilin 2 (PS2) have been found on early-onset familial AD (FAD). Apolipoprotein E is known as a risk factor on late-onset sporadic AD (SAD). Since high level of Aβ deposit is appeared in the patient brains of both FAD and SAD, it is considered that Aβ might be the major cause of AD. Because Aβ is generated from a larger precursor protein, designated APP, understanding APP processing is important. APP is processed through at least two different pathways. The α-secretory pathway involves α- and γ-secretases, generating two secreted protein fragments, sAPP αand p3. Alternatively, the secreted fragments sAPPβ and Aβ are generated out of the β-secretory pathway by the actions of β- and γ-secretases. In this review, mechanism of A βgeneration is discussed with focus on three secretases such as α-, β- and γ-secretases. Also, possible therapeutic approaches is discussed based on the information about basic research results of secretases.