본 연구의 목적은 알츠하이머질환(Alzheimer’s disease: AD) 동물 모델을 대상으로 트레드밀 운 동(Treadmill exercise: TE)과 환경강화(environmental enrichment: EE) 처치가 인지기능, 근 기능, 및 밀 착연접 단백질 발현에 미치는 영향을 확인하는데 있다. AD 동물 모델을 제작하기 위해 aluminum chloride(AlCl3)를 90일간(40mg/kg/하루) 투여 하였으며 동시에 TE(10-12m/min, 40-60min/day) 혹은 EE에 노출시켰다. 그 결과 AlCl3 투여에 의한 인지기능 저하와 근 기능 감소가 TE와 EE에 의해 완화된 것 으로 나타났다. 또한, TE와 EE는 AD 질환에서 나타나는 β-amyloid(Aβ), alpha-synuclein 및 tumor necrosis factor-α(TNF-α) 단백질의 발현 증가를 감소시킨 것으로 나타났다. 게다가 TE와 EE는 AlCl3 투여에 의해 감소된 밀착연접 단백질(Occludin, Claudin-5 및 ZO-1)의 발현을 통계적으로 유의하게 증가시킨 것으로 나타났다. 마지막으로 Aβ 단백질과 밀착연접 단백질과의 상관분석을 실시한 결과 부적 상 관관계(Occludin: r=-0.853, p=0.001; Claudin-5 : r=-0.352, p=0.915; ZO-1 : r=-0.424, p=0.0390) 로 나타났다. 따라서 이를 종합해 보면 TE 혹은 EE 처치는 AD에 나타나는 병리학적 특징들을 일부 완화 시켜 인지기능과 근 기능을 일부 개선 시킬 수 있는 효과적인 운동 방법이라고 생각된다.

Periodontitis, especially in its chronic form, is one of the leading causes of tooth loss, significantly affecting the quality of life in the modern era of aging society. Recent studies have revealed a potential correlation between periodontitis and various systemic diseases, including cardiovascular diseases and Alzheimer’s dementia (AD). With the body of epidemiologic evidence that links these separate disease entities, several lines of hypotheses have been postulated to provide mechanistic understandings that mostly comprises abnormal regulation of immunologic and inflammatory signaling. In this review, we revisit the experimental findings that describe virulence factors derived from Porphyromonas gingivalis, including gingipains and lipopolysaccharides, as well as their roles in the pathophysiology of AD. In addition, we address potential immunologic challenges imposed by this bacterial pathogen contributing to progression of AD.

Alzheimer's disease (AD) is one of the most common forms of dementia, affecting more than 50 million people globally. The onset of AD is linked to age, smoking, obesity, hypercholesterolemia, physical inactivity, depression, gender, and genetics of an individual. The accumulation of Aβ peptides and neurofibrillary tangles (NFTs) in the brain is one of the critical factors that lead to AD, which is known to disrupt neuronal signaling and causing neurodegeneration. As per the current understanding, inhibiting the accumulation of Aβ peptides and NFTs is crucial in the management/treatment of AD. Latest research studies show that nanoparticles have the potency of improving drug transport across the blood–brain barrier easily. Specifically, graphene quantum dots (GQDs), a type of semiconducting nanoparticles, have been established as effective inhibitors for blocking the aggregation of Aβ peptides. The small size of GQDs allows them to pass through the blood– brain barrier with ease. Moreover, GQDs have fluorescence properties, which can be used to detect the concentration of Aβ in vivo. In recent years, compared to other carbon materials, the low cytotoxicity and high biocompatibility of GQDs, give them an advantage in the suitability and clinical research for AD. In this manuscript, we have discussed the role of different types of nanoparticles in the transportation of encapsulated or co-assembled compound drugs for the treatment of AD and importantly, the role of GQDs in the diagnosis and management/treatment of AD.

Alzheimer’s disease (AD) is an irreversible and progressive neurodegenerative disease accompanied by aging, followed by memory impairment and cognitive decline. Although numerous attempts have been made to develop treatments for AD, most clinical trials have failed to delay or stop the progression of AD. Electroacupuncture (EA) is a complementary alternative medicine technique widely used to treat pain, inflammation, and neurodegenerative diseases. Additionally, blood-brain barrier (BBB) disruption is a known pathophysiology of neurodegenerative diseases, including AD. Moreover, amyloid beta deposition increases BBB permeability and produces inflammatory cytokines induced by glial activation. However, our previous study revealed that EA treatment at the Taegye acupoints (KI3) improves memory impairment through anti-neuroinflammation and increases glucose metabolism in 5XFAD mice. Therefore, we evaluated whether EA treatment at KI3 regulates BBB dysfunction in the prefrontal cortex of 5XFAD mice. For this study, 6.5-month-old 5XFAD mice were treated with EA stimulation at KI3 three times a week for two weeks. Western blotting, immunohistochemistry, and flow cytometry were used to evaluate the effects of EA treatment on BBB dysfunction. We found that EA stimulation attenuates BBB integrity by protecting BBB tight junction proteins (CD31, aquaporin 4, occludin, and claudin 5) in the prefrontal cortex of 5XFAD mice. In addition, EA treatment regulated inflammatory cytokines (IL-1α, IL-1β, IL-17, IL-23, IFN-ɣ, monocyte chemoattractant protein 1 (MCP-1), granulocyte-macrophage colony stimulating factors [GM-CSF], and IL-10) in the peripheral circulation of 5XFAD mice. Therefore, our data suggest that EA treatment could be a therapeutic agent for enhancing BBB dysfunction in AD.

본 연구는 알츠하이머(Alzheimer’s disease: AD) 형질전환 생쥐를 대상으로 저항성 운동 (resistance exercise: RE)이 해마의 베타 아밀로이드(β-amyloid: Aβ) 단백질 대사, 신경세포사멸 및 인지기능에 미치는 영향을 확인하는데 목적이 있다. AD 비 형질전환 생쥐(non-transgenic: non-tg, n=14) 와 형질전환 생쥐(transgenic: Tg, n=14)를 무선 배정하여 비 형질전환 생쥐 대조군 (non-tg-control: NTC, n=7), 비 형질전환 생쥐 저항성 운동군(non-tg-RE: NTRE, n=7), 형질전환 대조군(tg-control: TC, n=7) 및 형질전환 저항성 운동군(tg-RE: TRE, n=7)으로 구분하였다. RE는 특수 제작한 사다리 저항성 운동 기구를 사용하여 점진적으로 set 수를 증가시켜 총 8주간 실시하였다. 운동 후 인지기능 능력을 평 가하기 위한 수중미로검사와 Aβ 단백질 대사, 신경세포사멸 지표 및 SIRT1/PGC-1α 단백질 발현 수준 을 확인하였다. 수중미로검사 결과 거리와 시간 모두 TC 집단에서 유의하게 증가 되었지만 RE를 실시한 TRE 집단에서 거리와 시간이 감소 되어 인지능력이 개선된 것으로 확인되었다. 또한, TC 집단에서 증가 된 Aβ 단백질 발현은 RE를 통해 감소하는 것으로 나타났다. 신경세포사멸 관련 단백질인 Bcl-2/Bax ratio는 TC 집단에서 유의하게 감소되어 신경세포사멸이 증가 된 것으로 나타났지만 RE는 Bcl-2/Bax ratio을 증가시켜 신경세포사멸을 감소시킨 것으로 확인되었다. TC 집단에서 증가된 BACE1 및 ROCK1 과 감소된 ADAM10과 RARβ 단백질 발현은 RE를 통해 감소되거나 증가 된 것으로 나타났고, SIRT1/ PGC-1α 단백질 발현은 TC 집단에서 감소 되었지만 RE를 통해 증가 된 것으로 나타났다. 따라서 8주간 의 RE는 AD의 병리학적 특징인 Aβ 단백질 발현을 감소시키고 관련 생성 기전들을 조절하여 (SIRT1/PGC-1α 기전 활성, 아밀로이드 생성기전 억제, 비-아밀로이드 생성기전 활성) 신경세포사멸 억제시키고 결과적으로 인지기능을 개선 시킬 수 있는 효과적인 운동 방법이라고 생각된다.

The early-onset familial Alzheimer's disease (EOFAD/ FAD), the less common type of Alzheimer's disease (AD) currently affects a vast number of individuals worldwide. This type is being inherited as an autosomal dominant fashion. Missense mutations on Amyloid precursor protein (APP) and Presenilins 1 and 2 (PSEN1 & PSEN2) are known as major genetic factors in FAD. Conversely, missense mutations on microtubule-associated protein tau (MAPT) are also thought to involve. Up to date, several triple-transgenic animal models with muted forms of the human APP, PSENs and MAPT have been reported. Compared to other animals, canines are more emotional and their disease signs can be easily diagnosed. This attempt was to develop a triple transgenic canine model for the AD. We have obtained the coding sequences of APP, PSEN1 and MAPT from Dana-Farber/Harvard Cancer Center DNA resource core at HMS and incorporated several common AD mutations. The transgenic construct is composed of hNSE (ENO2) promoter-driven three AD genes fused together with modified 2A sequences. It was transfected into the canine fetal fibroblasts which were then used to perform somatic cell nuclear transfer (SCNT). The viable transgenic embryos were obtained after in vitro culture and the GFP was detected. In this study, we have successfully produced viable triple transgenic canine cloned embryos using SCNT technique. These transgenic canine embryos will be further developed into canines with FAD. The transgenic canines will be a good candidate in the AD research field.

목적 : 본 연구는 경도 알츠하이머병 치매환자에게 인지활동을 중심으로 신체활동, 정서활동을 병행한 복합중재 프로그램을 적용하였을 시 대상자의 인지기능 및 도구적 일상생활수행능력에 미치는 영향을 알아보고자 하였다. 연구방법 : 약물치료 중인 경도 알츠하이머병 치매환자 59명을 실험군 39명, 대조군 20명으로 무작위 배정하였다. 실험군에는 복합중재 프로그램, 대조군은 비 중재를 적용하였다. 중재는 실험군에 8주 동안 주 2회, 회기 당 110분씩 총 16회기의 중재를 실시하였다. 중재 전·후 비교를 위하여 치매선별용 간이정신상태 검사(Mini-Mental State Examination for Dementia Screening; MMSE-DS), 노인용 전산화 인지평가도구(Computer Cognitive Senior Assessment System for Elderly; COSAS), 한국형 도구적 일상생활활동 측정도구(Korean Instrumental Activities of Daily Living; K-IADL)를 사용하였다. 결과 : 약물을 복용 중인 경도 알츠하이머병 치매환자 59명 중 복합중재 프로그램을 실시한 집단은 비 중재를 실시한 집단과 비교하여 인지기능과 도구적 일상생활수행능력이 통계적으로 유의미하게 향상되었다(p<.01). 결론 : 복합중재 프로그램은 경도 알츠하이머병 치매환자의 인지기능, 도구적 일상생활수행능력의 유지 및 향상에 효과적인 중재 프로그램임을 제시하였다.

Alzheimer's disease (AD) has caused by expression of amyloid precursor protein (APP), Tau and presenilin (PS) as known as plaques and tangle accumulation. AD transgenic porcine model is necessary for preclinical testing of therapeutic agent because of similar metabolic system between porcine and human. The objective of study was to generate AD transgenic pig by somatic cell nuclear transfer (SCNT) with multi-cistronic vector system. AD multi-cistronic vector was 6 well-known mutation on 3 AD related genes, hAPP (K670N/M671L, I716V, V717I), hTau (P301L) and hPS1 (M146V, L286P). Establishment of AD transgenic cell lines was used from Jeju black pig ear fibroblast cells (JB-PEFAD) with the AD multi-cistronic vector. The JB-PEFAD cell was confirmed on mRNA expression, protein synthesis of hAPP, hTau and hPS1 and identification of integration and karyotype. Although fusion rate was no difference in SCNT with JB-PEF AD (SCNTAD) embryos, cleavage and blastocyst formation rates were slightly lower than in SCNT with non-transgenic JB-PEF (SCNTnon-TG). Individual SCNTAD blastocysts were detected hAPP, hTau and hPS1 genomic integration which showed 93.2% (n=30) efficiency in genomic DNA (gDNA) level. It will give us a possibility to develop porcine animal model for AD study in the future.

Alzheimer’s disease (AD) is an age-related neurodegenerative disease characterized by extensive loss of synaptic connections, neuronal death, and the presence of extracellular amyloid plaques and intracellular neurofibrillary tangles (iNFTs). The extracellular amlyoid plaques are mainly composed of the amyloid beta (Aβ) peptide which formed by proteolytic processing of the amyloid precursor protein (APP). Aβ42peptide oligomerizes, is neurotoxic and readily forms aggregates that accumulate in the brain to form plaques. These oligomers are thought to cause inflammation, oxidative stress and apoptosis, thereby resulting in synaptic and neuronal loss. Although AD is neurodegenerative disorder, current therapies designed to treat it still demonstrate limited efficacy. Silkworm (Bombyx mori) has long been used as food and medicine in Asian countries which is reputed for the treatment of numerous neurological disorders including AD. In this study, we use Drosophila melanogaster which is expressed the human AD-associated protein APP695, BACE and MAPT as the model and initially investigate whether silkworm powder food has positive effect on flies expressing Alzheimer’s status as well as makes the improvement in disease condition by using this AD fly model (This work was carried out with the support of the Cooperative Research Program for Agriculture Science & Technology Development (Project title: Elucidation the health improvement effects of boiled silk worm larvae, Project No: PJ01082801) Rural Development Administration)

The human β-amyloid (Aβ) cleaving enzyme (BACE-1) is a target for Alzheimer’s disease (AD) treatments. This study was conducted to determine if acacetin extracted from the whole Agastache rugosa plants had anti-BACE-1 and behavioral activities in Drosophila AD models and to determine acacetin’s mechanism of action. Acacetin (100, 300, and 500 μM) rescued amyloid precursor protein (APP)/BACE1-expressing flies and kept them from developing both eye morphology (dark deposits, ommatidial collapse and fusion, and the absence of ommatidial bristles) and behavioral (motor abnormalities) defects. The RT-PCR and Western blot analysis revealed that the protective effect of acacetin on Aβ production is mediated by transcriptional regulation of BACE-1 and APP, resulting in decreased APP protein expression and BACE-1 activity, and reduced Aβ production by interfering with BACE-1 activity and APP synthesis, resulting in a decrease in the levels of the APP carboxy terminal fragments and the APP intracellular domain, and finally, resulting in a decrease in the number of amyloid plaques.

Alzheimer’s disease (AD) is the most common type of presenile and senile dementia. Human β-amyloid precursor cleavage enzyme (BACE-1) is a key enzyme responsible for amyloid plaque production. We assessed anti-BACE-1 and behavioral activities of curcuminoids from Curcuma longa, curcumin (CCN), demethoxycurcumin (DMCCN), and bisdemethoxycurcumin (BDMCCN) against AD fly models. Neuro-protective ability of curcuminoids was assessed using fly model system overexpressing BACE-1 and its substrate APP in compound eyes and entire neurons. BDMCCN has the strongest inhibitory activity toward BACE-1 with 17 μM IC50, which was 20 and 13 times lower than those of CCN and DMCCN respectively. Expression of APP/BACE-1 resulted in the progressive and measurable defects in morphology of eyes and locomotion. Supplementing diet with either 1 mM BDMCCN or CCN rescued APP/BACE1 expressing flies and kept them from developing both morphological and behavioral defects. Structural characteristics and hydrophobicity appear to play a role in determining inhibitory potency of curcuminoids on BACE-1.

This study is intended to examine the tDCS and Morris Water maze training in Alzheimer’s disease(AD) rats on Tau protein expression. Experiment groups were divided into four groups and assigned 16 rats to each group. Group Ⅰ was a control group(AD induced by scopolamine); Group Ⅱ was a experimental control group(AD injured by scopolamine and treatment tacrine); Group Ⅲ was a group of tDCS application after AD injured by scopolamine; Group Ⅳ was a group of morris water maze training after AD injured by scopolamine. In cognition test, the outcome of group Ⅱ was significantly lower than the groups(p<.001). and group Ⅲ, Ⅳ were significantly low result at 14 days(p<.05). In histological finding, the experimental groups were destroy of micro vessels and finding of cell atropy and swelling. Group Ⅲ, Ⅳ were decreased in degeneration of liver and kidney cells. In immuno- histochemistric response of BDNF and tau protein in hippocampus, BDNF expression of Group Ⅱ was more increase than the other groups. and increase of BDNF expression was Ⅲ, Ⅳ were higher than group Ⅰ at 21 days. Tau protein expression of Group Ⅱ was more decrease than the other groups. and decrease of Tau protein expression was Ⅲ, Ⅳ were lower than group Ⅰ at 21 days. These result suggest that improved tDCS and morris water maze training after scopolamine induced is associated with dynamically altered expression of BDNF and Tau protein in hippocampus and that is related with cognitive function.

본 연구에서는 대표적인 퇴행성 신경질환인 알츠하이머성 치매에 대한 마늘 물, 100% 메탄올, 디 클로로메탄 추출물들의 acetylcholinesterase (AChE) 저해 및 신경세포 보호효과를 조사하였다. 마늘 디클로로메탄 추출물은 농도 의존적으로 AChE를 저해하는 것으로 나타났으며, IC50은 36.1 μg/mL로 나타났다. MTT reduction assay를 이용해 amyloid β protein (Aβ) 유도성 신경세포 독성에 대한 신경 세포 보호효과를 측정한 결과, 세 가지 마늘 추출물들은 대부분 40% 미만의 세포생존율을 보였고 이 결과는 Aβ 유도성 신경세포 독성보다 상대적으로 더 높은 세포독성을 보여주었다. LDH assay에 서는 마늘 물 추출물이 37%의 LDH 방출량을 나타내 200 μM의 vitamin C과 유사한 세포막손상 보 호효과를 보였다. 마지막으로 neutral red uptake assay를 실시한 결과, MTT reduction assay와 마찬가 지로 모든 마늘 추출물들에서 세포생존율의 감소를 확인하였으며 특히 디클로로메탄 추출물의 경우 현저하게 낮은 세포생존율을 나타내었다. AChE 저해활성을 갖는 마늘 디클로로메탄 추출물로부터 얻은 column fractionations에 함유된 생리활성물질을 탐색하기 위해 HPLC 분석을 실시하였으며, 마 늘 98:2 fraction의 LC-MS 분석을 통하여 allyl methyl disulfide, diallyl monosulfide, diallyl disulfide로 추정되는 물질군이 확인되었다.

The present study was carried out to establish an animal model, displaying long-term learning and memory dysfunction, since single intracerebroventricular (icv) injection of amyloid β peptide (Aβ) causes a short-term memory impairment. Male ICR mice were fed a high-cholesterol diet (HCD) containing 3% cholesterol, 1% corn oil and 0.5% cholic acid, and 1 week later, icv injected with Aβ_1-42 (5 μg/head). Learning/ memory function was assessed via passive avoidance performances 1 day and 2, 4, and 6 weeks after Aβ_1-42 injection, in addition to blood biochemical analyses for lipid profiles and hepatic function. Total cholesterol, lowdensity lipoproteins and hepatic dysfunction parameters markedly increased, while high-density lipoproteins were reduced following HCD feeding. Whereas single injection of Aβ induced temporary memory loss 1 day after administration, exhibiting full recovery after 2 weeks, Aβ treatment in combination with HCD feeding lasted the learning/memory impairment up to 6 weeks. Therefore, it is suggested that hypercholesterolemia augments Aβ-induced memory loss, and that Aβ injection plus HCD feeding could be a long-term memorydeficit model suitable for long-term treatment with drugs or stem cells.

알츠하이머병은 치매를 일으키는 가장 흔한 퇴행성 뇌 질환이다. 뇌에 축적되는 베타 아밀로이드 단백질은 기억력감퇴, 언어능력 저하등 일상생활 수행 능력이 어렵게 된다. 베타 아밀로이드 플라그 농도는 인지 장애를 가진 성인환자에서 알츠하이머 질환과 인지장애의 다른 원인인지를 평가하는 데 사용된다. 베타아 밀로이드 단백질에 대한 높은 민감성과 특이성을 가진 18F-Florbetaben을 이용하여 알츠하이머병을 조기진단에 유용성을 알아보고자 한다. 18F-FDG Brain 영상에서 특이소견 없음을 보인다. 그리고 MR-Brain 영상에서 해마의 위축이 없는 것으로 보였다. 하지만 18F-Florobetaben에서 베타 아밀로이드의 섭취는 알츠하이머 병의 진전이 되고 있음을 알려준다. 따라서, 18F-Florobetaben은 알츠하이머병을 조기 진단하는 데 매우 유용하다.

인삼, 목과 혼합추출액이 βA로 유도된 AD 병태 모델에 미치는 영향을 관찰한 결과, 다음과 같은 결론을 얻었다. 1. 인삼, 목과 혼합추출액은 AD 병변 뇌조직의 허혈(虛血) 상태를 유의성 있게 개선하였고 허혈(虛血)로 인한 뇌조직 손상을 억제하였다. 2. 인삼, 목과 혼합추출액은 AD 병변 뇌조직의 면역조직화학 염색법으로 Tau 단백질, GFAP 단백질, presenilin 1/presenilin 2 단백질의 발현 억제를 확인하였다. 이상의 결과로 미루어 보아 인삼, 목과 추출액은 AD의 예방과 치료에 사용될 수 있을 것으로 판단되며 정확한 기전에 대한 연구와 AD 치료에 있어서 인삼, 목과 혼합추출액의 임상적 활용에 대한 연구가 향후 지속적으로 이루어져야 할 것으로 사료된다.