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.

Raphanus sativus var. hortensis f. raphanistroides Makino (Korean wild radish [WR]) are root vegetables belonging to the Brassicaceae family. These radish species mostly grow in sea areas in Asia, where they have been traditionally used as a medicinal food to treat various diseases. To investigate the effect of WR on neuronal cell death in SH-SY5Y cells, betaamyloid was used to develop the cell death model. WR attenuated neuronal cell death in SH-SY5Y and regulated the mitogen-activated protein kinase (MAPK) signaling. WR extract also inhibited acetylcholinesterase inhibitor activity. Additionally, the WR treatment group ameliorated the behavior of the memory-impaired mice in a scopolamine-induced mouse model. In the behavior test, WR treated mice showed shorter escape latency and swimming distance and improved the platform-crossing number and the swimming time within the target quadrant. Furthermore, WR prevented histological loss of neurons in hippocampal CA1 regions induced by scopolamine. This study shows that WR can prevent memory impairment which may be a crucial way for the prevention and treatment of memory dysfunction and neuronal cell death.

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.

알츠하이머병의 발병원인과 기전에 대하여 많은 연구가 진행되었으나, 아직까지 완전히 밝혀지지 않고 있다. 이에 본 연구에서는 STZ로 유도된 세포독성으로부터 노인성 질병의 예방과 항산화 효과로 잘 알려진 비타민 C를 이용하여 SH-SY5Y 신경세포 내 보호 기전을 살펴보고자 하였다. 본 연구 결과에 의하면, STZ를 SH-SY5Y 신경세포에 처리하였을 때, 세포사멸이 유도되는 것을 확인하였으며, 비타민C를 전처리함으로써 세포생존도가 증가하는 것을 확인하였다. 비타민 C가 신경세포를 보호하는 기전을 알아보기 위하여 세포자멸사 과정에서 신호전달을 통해 다양한 유전자를 발현시키는 MAPKs의 인산화를 살펴보았다. 비타민 C 처리시 ERK의 인산화가 증가하며, 세포증식을 유도하는 것으로 확인하였으며, ERK와는 반대로 염증, 세포사멸과 관련된 JNK의 인산화는 비타민 C에 의해 인산화가 억제되는 것으로 확인되었다. 또한 STZ는 Bax 단백질의 발현 증가와 Bcl-2 단백질의 발현을 감소시켰으며, apoptosis antibody array로 확인한 결과, Cytochrome C가 유도됨을 확인하였다. 이뿐만 아니라, 비타민 C 처리에 의해 Bcl-2가 증가하여 세포사멸이 억제되는 것을 확인하였으며, 항산화 효소인 Sod-1의 발현을 증가하는 것 또한 확인하였다. 이는 비타민 C가 항산화 방어체계를 강화시켜 STZ에 의한 세포손상을 보호하는 것으로 사료된다. 본 연구를 통하여 STZ로 유도된 SH-SY5Y 신경세포 손상 에서 비타민 C가 여러 기전을 통하여 세포자멸사를 억제하여 세포를 보호하는 효과가 있는 것을 확인할 수 있었다. 그러나 연구는 일부 기전들만을 확인한 것으로 추후 연구에서는 다양한 비타민 C의 농도 및 처리시간에 따른 기전의 차이를 분석하고, 실험동물을 통한 검증 및 스트렙토조토신에 의한 아밀로이드베타와 타우의 관련성을 확인하고자 한다.

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.

An assessment was made of beta-site amyloid precursor protein (APP) cleaving enzyme (BACE1) inhibitory, feeding, climbing activities and lifespan of the diarylalkyls curcumin (CCN), demethoxycurcumin (DCCN) and bisdemethoxycurcumin (BDCCN) identified in the rhizomes of Curcuma longa. Based on IC50 values, BDCCN (0.024 mM) was the most inhibitory constituent, followed by DCCN (0.31 mM) and CCN (0.59 mM). Overall the three curcuminoids were significantly less inhibitory than BACE1 inhibitor IV isophthalamide (8.5 × 10-5 mM). The expression of human APP and BACE1 in compound eye of Drosophila melangaster presented rough abnormal ommatidial lattice. Co-expression of APP and BACE1 within the developing nervous system of drosophila showed climbing defects. These transgenic flies kept on media containing 1 mM of CCN and BDCCN were observed to ameliorate eye degeneration, significantly suppress locomotive dysfunctions, and increase media life time, as well as isophthalamide. CCN and BDCCN as human BACE1 inhibitory constituents may be used as potential therapeutics or lead molecules to develop Alzheimer's disease treatment drugs.

Alzheimer’s disease (AD) is a fatal disorder wherein patients suffer from sensory, motor, and cognitive loss. Currently, the identification and validation of biomarkers for diagnosing AD and other forms of dementia are increasingly important. Olfactory dysfunction is present in patients diagnosed with Alzheimer’s disease or idiopathic Parkinson's disease. Alzheimer’s patients show neuropathological changes in areas of the brain central to the olfactory processing center, suggesting the theoretical importance and potential diagnostic utility of investigating functional changes in olfaction in these patients. However, the usefulness of olfactory screens to serve as informative indicators of Alzheimer’s is precluded by the lack of knowledge regarding neural and molecular mechanisms underlying olfactory dysfunction onto Alzheimer's diseases. To test these ultimate questions, we used molecular and electrophysiological recording techniques to find out the difference of olfactory responses and AD related protein expression patterns by using fly model, Drosophila melanogaster that over-expresses the human β -amyloid, tau protein. We postulated that such flies would present with progressive olfactory impairments compared with age-matched wild type control flies. In this study, our hypothesis is that there is a correlation between olfactory deficits and the spatial expression pattern of β-amyloid and tau protein deposition. Therefore, we demonstrate a specific concentration of lesions in central olfactory structures such as antenna and Maxillary palps. Our study indicates that deficits on olfactory identification may occur in AD, which will be valuable as an indicator of neuropathogenesis.

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.

This study was conducted to select candidates from plant resources for the purpose of improving or treating Alzheimer’s disease, a type of dementia. One hundred and eighty-four plant extracts at a final concentration of 100 ㎍/㎖ were screened to determine their capacity to inhibit acetylcholinesterase (AChE) by in vitro assay. From this AChE assay, seven plant extracts - including methanol ext. and water ext. of Phellaodendron amurense Rupr. (bark), methanol ext. of Nelumbo nucifera Gaertn (stamen/ovary), methanol ext. of Persicaria tinctoria H. GROSS (flower), methanol ext. of Coptis chinensis (rhizome), ethanol ext. of Cinnamomum cassia Blume(bark) and ethanol ext. of Carthamus tinctorius L. (fruit) - showed effective inhibition activity ranging from 18.7% to 63.1%. The selected extracts were testified their inhibition activities on AChE and BuChE (butyrylcholinesterase) at concentrations of 25, 50, 100, 200 ㎍/㎖. In the AChE assay, five extracts including methanol ext. of Nelumbo nucifera Gaertn. (stamen/ovary), methanol ext. of Persicaria tinctoria H. GROSS (flower), methanol ext. of Coptis chinensis (rhizome), methanol ext. and water ext. of Phellaodendron amurense Rupr. (bark) showed inhibition activity of 15.0%~73.5%, 19.5%~63.5%, 81.6%~58.5%, 69.9%~80.5%, and 54.8%~78.3%, respectively, at concentrations of 25, 50, 100, 200 ㎍/㎖. In the BuChE assay, the extracts of Nelumbo nucifera Gaertn. (stamen/ovary), Persicaria tinctoria H. GROSS (flower), and Coptis chinensis (rhizome) showed inhibitory capacities of 58.9~81.6%, 45.8%~72.4%, and 33.1%~55.4% at concentrations of 25, 50, 100, 200 ㎍/㎖, respectively. In conclusion, it is suggested that Nelumbo nucifera Gaertn. (stamen/ovary), Persicaria tinctoria H. GROSS, Coptis chinensis (rhizome) and Phellaodendron amurense Rupr. (bark) could be selected as candidate materials for improving or treating Alzheimer’s disease on the basis of further study.