老化における食細胞の役割に関する研究
キーワード：老化　食細胞
2005.05～2010.05.

慢性全身脳炎症による脳機能に及ぼす影響
キーワード：全身炎症、脳炎症、神経免疫、脳血管内皮細胞、髄膜細胞、脳老化
1996.10.

ジンジバリス菌による脳バリア微環境破綻を介したアルツハイマー病誘発機序の解明
2022.04～2025.03, 代表者：武　洲, 九州大学歯学研究院, 九州大学（日本）
臨床研究により歯周病の罹患とアルツハイマー病（(AD)の病態進行は正相関し、歯周病菌病原菌のP.gingivalis菌とその成分がADの剖検脳内に検出された。このため「歯周病がADの増悪因子」と提唱されるが、ADの早期病態への関与はまだ不明である。 私たちは長年一貫して、歯周病を含む全身炎症の脳機能に及ぼす影響について解析しており、P.gingivalis菌/LPSにより正常な中年マウスにAD様脳病態ならびにその脳病態を促す全身病態が誘発されることを明らかにしてきた。最近、P.gingivalis菌による全身で誘発されるアミロイド（A）が循環血と脳のインタフェースである脳バリア細胞を介して脳内に輸入されることを見出し、注目されている。シナプス障害はADの発症する前の超早期病態であり、その介入はAD発症を遅らせるに有効なアプローチと考えられる。そこで本研究ではP.gingivalis菌による、脳バリア微環境ホメオスタシス破綻、 シナプス障害 、 学習・記憶機能への影響について検討を行い、歯周病のAD早期病態への関与の検証とその分子機構を明らかにする。 .

主要著書

1.	武　洲, ≪ヒト常在菌叢と生理機能・全身疾患≫ （監修者　落合邦康）, ジーエムジー出版、東京、日本, pp. 257-265., 2020.08.
2.	武　洲, 歯周病によるアリツハイマ―病の関与メカニズム　≪アリツハイマ―病－発症メカニズムと新規診断法・創薬・治療開発, エヌ・ティ－エス株式会社、東京、日本, pp. 40-44, 2018.06.
3.	Nakanishi H, Wu Z, Microglia-aging and pain: Microglial cathepsin B-dependent IL-1 production, In: Interleukin-1: Genetics, Inflammatory Mechanisms and Role in Disease, Nova Science Publishers, pp. 143-156, 2013.06.
4.	Wu Z, Nakanishi H, TNF-a signaling and cathepsin B, In: Tumor Necrosis Factor: Structure. Enzyme Regulation and Role in Health and Disease, Nova Science Publisher Inc, pp. 113-128, 2013.06.
5.	Zhou Wu and Hiroshi Nakanishi, Neuroimmunology Research Focus Chapter 4 Age-Dependent Differential Activation Profiles of Glial Cell by the Leptomeninges During Systemic Inflammation, Nova Science Pulishers, Inc., pp. 101-118., 2007.09.

主要原著論文

1.	Muzhou Jiang, Xinwen Zhang, Xu Yan, Shinsuke Mizutani, Haruhiko Kashiwazaki, Junjun Ni† and Zhou Wu, GSK3β is involved in promoting Alzheimer’s disease pathologies following chronic systemic exposure to Porphyromonas gingivalis lipopolysaccharide in amyloid precursor proteinNL-F/NL-F knock-in mice., Brain Behav Immun., 10.1016/j.bbi.2021.08.213, 98, 1-12, 2021.09.
2.	Wanyi Huang, Fan Zeng, Yebo Gu, Muzhou Jiang, Xinwen Zhang, Xu Yan, Tomoko Kadowaki, Shinsuke Mizutani, Haruhiko Kashiwazaki, Junjun Ni† and Zhou Wu, Porphyromonas gingivalis infection induces synaptic failure via increased IL-1βproduction in leptomeningeal cells, J. Alzheimer's Dis., 10.3233/JAD-210031., 83, 2, 665-681, 2021.06.
3.	Zng F, Liu Y, Huang W, Qing H, Kadowaki T, Kashiwazaki H, Ni J, Wu Z, Mediates Cerebrovascular-related Amyloid β Accumulation After Porphyromonas Gingivalis Infection, Journal of Neurochemistry, 10.1111/jnc.15096, 1-13, 2020.06, Cerebrovascular-related amyloidogenesis is found in over 80% of Alzheimer’s disease (AD) cases, and amyloid β (Aβ) generation is increased in the peripheral macrophages during infection of Porphyromonas gingivalis (P. gingivalis), a causal bacterium for periodontitis. In the present study, we focused on receptor for advanced glycation end products (RAGE), the key molecule involves in Aβ influx after P. gingivalis infection to test our hypothesis that Aβ transportation from periphery into the brain, known as “Aβ influx”, is enhanced by P. gingivalis infection. Using cultured hCMEC/D3 cell line, in comparison to uninfected cells, directly infection with P. gingivalis (multiplicity of infection, MOI=5) significantly increased a time-dependent RAGE expression resulting in a dramatic increase of Aβ influx in the hCMEC/D3 cells; the P. gingivalis-upregulated RAGE expression was significantly decreased by NF-κB and Cathepsin B (CatB)-specific inhibitors, and the P.gingivalis-increased IκBα degradation was significantly decreased by CatB specific inhibitor. Furthermore, the P. gingivalis-increased Aβ influx was significantly reduced by RAGE-specific inhibitor. Using 15-month-old mice (C57BL/6JJmsSlc, female), in comparison to non-infection mice, systemic P. gingivalis infection for 3 consecutive weeks (1×108 CFU/mouse, every 3 days, intraperitoneally) significantly increased the RAGE expression in the CD31-positive endothelial cells and the Aβ loads around the CD31-positive cells in the mice’s brains. The RAGE expression in the CD31-positive cells was positively correlated with the Aβ loads. These observations demonstrate that the upregulated RAGE expression in cerebral endothelial cells mediates the Aβ influx after P. gingivalis infection, and CatB plays a critical role in regulating the NF-κB/RAGE expression..
4.	Jiang M, Meng J, Zeng F, Qing H, Hook G, Hook V, Wu Z, Ni J, Cathepsin B Inhibition Blocks Neurite Outgrowth in Cultured Neurons by Regulating Lysosomal Trafficking and Remodeling, Journal of Neurochemistry, 10.1111/jnc.15032, 1-13, 2020.04.
5.	Nie, Ran; Wu, Zhou; Ni, Junjun; Zeng, Fan; Yu, Weixian; Zhang, Yufeng; Kadowaki, Tomoko ; Kashiwazaki, Haruhiko; Teeling, Jessica L. ; Zhou, Yanmin, Porphyromonas gingivalis Infection Induces Amyloid-β Accumulation in Monocytes/Macrophages, Journal of Alzheimer's Disease, 72(2):479-494, 2019.11, Abnormal accumulations of amyloid-β (Aβ) in the brain is the most significant pathological hallmark of Alzheimer’s disease (AD), and we have found that chronic systemic exposure to lipopolysaccharide of P. gingivalis induces the brain Aβ accumulation in the middle-aged mice. On the other hand, recent research has shown that circulating Aβ are transferred into the brain, however, the involvement of chronic systemic P. gingivalis infection in peripheral Aβ metabolism is unknown. We hypothesized that chronic P. gingivalis infection expands the Aβ pools in peripheral inflammatory tissues which contributes to the accumulation of Aβ in the brain during periodontitis. We conducted immunofluorescence and biochemical analyses on the molecules of inflammation and Aβ metabolism in the chronic systemic P. gingivalis infected middle-aged mice and the P. gingivalis infected cultured monocyte/macrophages (RAW264.7 cells). We showed that the increased expressions of IL-1β, APP770, CatB, Aβ1-42 and Aβ3-42 were mainly co-localized with macrophages in the liver of P. gingivalis infected mice. Blocking CatB and NF-κB by their specific inhibitors significantly inhibited the P. gingivalis infection induced expressions of IL-1β, APP770, Aβ1-42 and Aβ3-42 in cultured RAW264.7 cells. Additionally, the expressions of APP770, CatB, Aβ1-42 and Aβ3-42 were determined in the macrophages of gingival tissues form patients of periodontitis. These findings indicate that chronic systemic P. gingivalis infection induces Aβ accumulation in the inflammatory monocytes/macrophages via activating CatB/NF-κB signaling, thus suggests monocytes/macrophages serve as a circulation Aβ pool during periodontitis. CatB should be a novel therapeutic target for preventing periodontitis-related AD initiation and pathology process..
6.	Junjun Ni, Hiro Take, Veronika Stoka, Jie Meng, Yoshinori Hayashi, Christoph Peters, Hong Qing, Vito Turk, Hiroshi Nakanishi, Increased expression and altered subcellular distribution of cathepsin B in microglia induce cognitive impairment through oxidative stress and inflammatory response in mice, Aging cell, 10.1111/acel.12856, 18, 1, 2019.02, [URL].
7.	Zhu A, Wu Z, Zhong X, Ni J, Li Y, Meng J, Du C, Zhao X, Nakanishi H, Wu S, Brazilian Green Propolis Prevents Cognitive Decline into Mild Cognitive Impairment in Elderly People Living at High Altitude, J. Alzheimer's Dis, 63(2), 551-560, 2018.06.
8.	Hiro Take, Junjun Ni, Yicong Liu, Jessica L. Teeling, Fumiko Takayama, Alex Collcutt, Paul Ibbett, Hiroshi Nakanishi, Cathepsin B plays a critical role in inducing Alzheimer's disease-like phenotypes following chronic systemic exposure to lipopolysaccharide from Porphyromonas gingivalis in mice, Brain, Behavior, and Immunity, 10.1016/j.bbi.2017.06.002, 65, 350-361, 2017.10, [URL].
9.	Junjun Ni, Hiro Take, Jie Meng, Aiqin Zhu, Xin Zhong, Shizheng Wu, Hiroshi Nakanishi, The Neuroprotective Effects of Brazilian Green Propolis on Neurodegenerative Damage in Human Neuronal SH-SY5Y Cells, Oxidative Medicine and Cellular Longevity, 10.1155/2017/7984327, 2017, 2017.01, [URL].
10.	NI JUNJUN, Wu Z, Christoph Peterts, Kenji, Yamamoto, Hong Qin, Hiroshi Nakanishi, The critical role of proteolytic relay through cathepsins B and E in the phenotypic change of microglia/macrophage, J. Neurosci, 10.1523/JNEUROSCI.1599-15.2015, 35, 36, 12488-501, 2015.09.
11.	Liu Y, Wu Z, Zhang XW, Ni J, Yu W, Zhou Y, Hiroshi Nakanishi, Leptomeningeal cells transduce peripheral macrophages inflammatory signal to microglia in reponse to Porphyromonas gingivalis LPS., Mediators Inflamm., 10.1155/2013/407562, 2013:407562, 2013.12.
12.	Hiro Take, Li Sun, Sadayuki Hashioka, Sheng Yu, Claudia Schwab, Ryo Okada, Yoshinori Hayashi, Patrick L. McGeer, Hiroshi Nakanishi, Differential pathways for interleukin-1β production activated by chromogranin A and amyloid β in microglia, Neurobiology of Aging, 10.1016/j.neurobiolaging.2013.05.018, 34, 12, 2715-2725, 2013.12, [URL], Although chromogranin A (CGA) is frequently present in Alzheimer's disease (AD), senile plaques associated with microglial activation, little is known about basic difference between CGA and fibrillar amyloid-β (fAβ) as neuroinflammatory factors. Here we have compared the interleukin-1β (IL-1β) production pathways by CGA and fAβ in microglia. In cultured microglia, production of IL-1β was induced by CGA, but not by fAβ. CGA activated both nuclear factor-κB (NF-κB) and pro-caspase-1, whereas fAβ activated pro-caspase-1 only. For the activation of pro-caspase-1, both CGA and fAβ needed the enzymatic activity of cathepsin B (CatB), but only fAβ required cytosolic leakage of CatB and the NLRP3 inflammasome activation. In contrast, fAβ induced the IL-1β secretion from microglia isolated from the aged mouse brain. In AD brain, highly activated microglia, which showed intense immunoreactivity for CatB and IL-1β, surrounded CGA-positive plaques more frequently than Aβ-positive plaques. These observations indicate differential pathways for the microglial IL-1β production by CGA and fAβ, which may aid in better understanding of the pathological significance of neuroinflammation in AD..
13.	Wu, Z., Tokuda, Y., Zhang, X-W., Nakanishi, H., Age-dependent responses of glial cells and leptomeninges during sytemic inflammation., Neurobiology of Disease, 32, 543-551, 2008.10.

主要総説, 論評, 解説, 書評, 報告書等

1.	Dehao Shang, Minghao Huang, Biyao Wang, Xu Yan, ＠Zhou Wu, Xinwen Zhang, mtDNA Maintenance and Alterations in the Pathogenesis of Neurodegenerative Diseases, Current Neuropharmacology, 10.2174/1570159X20666220810114644, 2023.04, Considerable evidence indicates that the semiautonomous organelles mitochondria play key roles in the progression of many neurodegenerative disorders. Mitochondrial DNA (mtDNA) encodes components of the OXPHOS complex but mutated mtDNA accumulates in cells with aging, which mirrors the increased prevalence of neurodegenerative diseases. This accumulation stems not only from the misreplication of mtDNA and the highly oxidative environment but also from defective mitophagy after fission. In this review, we focus on several pivotal mitochondrial proteins related to mtDNA maintenance (such as ATAD3A and TFAM), mtDNA alterations including mtDNA mutations, mtDNA elimination, and mtDNA release-activated inflammation to understand the crucial role played by mtDNA in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. Our work outlines novel therapeutic strategies for targeting mtDNA..
2.	Gregory Hook, Thomas Reinheckel, Junjun Ni, ＠Zhou Wu, Mark Kindy, Christoph Peters, and Vivian Hook, Cathepsin B Gene Knockout Improves Behavioral Deficits and Reduces Pathology in Models of Neurological Disorders, 10.1124/pharmrev.121.000527, 2022.07, Cathepsin B (CTSB) is a powerful lysosomal protease. This review evaluated CTSB gene knockout (KO) outcomes for amelioration of brain dysfunctions in neurologic diseases and aging animal models. Deletion of the CTSB gene resulted in significant improvements in behavioral deficits, neuropathology, and/or biomarkers in traumatic brain injury, ischemia, inflammatory pain, opiate tolerance, epilepsy, aging, transgenic Alzheimer’s disease (AD), and periodontitis AD models as shown in 12 studies. One study found beneficial effects for double CTSB and cathepsin S KO mice in a multiple sclerosis model. Transgenic AD models using amyloid precursor protein (APP) mimicking common sporadic AD in three studies showed that CTSB KO improved memory, neuropathology, and biomarkers; two studies used APP representing rare familial AD and found no CTSB KO effect, and two studies used highly engineered APP constructs and reported slight increases in a biomarker. In clinical studies, all reports found that CTSB enzyme was upregulated in diverse neurologic disorders, including AD in which elevated CTSB was positively correlated with cognitive dysfunction. In a wide range of neurologic animal models, CTSB was also upregulated and not downregulated. Further, human genetic mutation data provided precedence for CTSB upregulation causing disease. Thus, the consilience of data is that CTSB gene KO results in improved brain dysfunction and reduced pathology through blockade of CTSB enzyme upregulation that causes human neurologic disease phenotypes. The overall findings provide strong support for CTSB as a rational drug target and for CTSB inhibitors as therapeutic candidates for a wide range of neurologic disorders..
3.	Zhen Xie, Jie Meng, Zhou Wu, Hiroshi Nakanishi, Yoshinori Hayashi, Wei Kong, Fei Lan, Narengaowa, Qinghu Yang, Hong Qing, Junjun Ni, The Dual Nature of Microglia in Alzheimer's Disease: A Microglia-Neuron Crosstalk Perspective., Neuroscientist, doi: 10.1177/10738584211070273, 2022.03.
4.	武　洲, 歯周病がアルツハイマー病の原因に？！歯科から始めるザ・認知症予防, nico QUINTESSENCE PUBLISHING, ISSNI1881-7556 p10-23, 2021.07.
5.	武　洲, 認知症に備える　, Re　一般財団法人　建築保全センター, 2021.05, 認知症の7割を占めるアルツハイマー型認知症（Alzheimer's disease,AD）の9割は加齢に連れて発症し、わが国の認知症増加の一因と考えられる。脳内免疫細胞のミクログリア異常に惹起される脳内炎症がアミロイドβ（A）蓄積を促す。一方、関節リウマチなど疾患に増大される全身炎症がミクログリア異常を起こし、ADの発症や病態進行を加速することも分かっている。中高年の8割に発症する歯周病は全身に炎症を起こし、近年ADへの関与が注目されている。 本稿では歯周病のADへの関与機序を解説し、認知症の備えに口を衛（まもる）から脳を守る「口健力」創出という理念を提案する。.
6.	Junjun Ni, ＠Zhou Wu., Inflammation Spreading: Negative Spiral Linking Systemic Inflammatory Disorders and Alzheimer's Disease, Front Cell Neurosci., doi: 10.3389/fncel.2021.638686. eCollection 2021, 2021.05, As a physiological response to injury in the internal body organs, inflammation is responsible for removing dangerous stimuli and initiating healing. However, persistent and exaggerative chronic inflammation causes undesirable negative effects in the organs. Inflammation occurring in the brain and spinal cord is known as neuroinflammation, with microglia acting as the central cellular player. There is increasing evidence suggesting that chronic neuroinflammation is the most relevant pathological feature of Alzheimer's disease (AD), regulating other pathological features, such as the accumulation of amyloid-β (Aβ) and hyperphosphorylation of Tau. Systemic inflammatory signals caused by systemic disorders are known to strongly influence neuroinflammation as a consequence of microglial activation, inflammatory mediator production, and the recruitment of peripheral immune cells to the brain, resulting in neuronal dysfunction. However, the neuroinflammation-accelerated neuronal dysfunction in AD also influences the functions of peripheral organs. In the present review, we highlight the link between systemic inflammatory disorders and AD, with inflammation serving as the common explosion. We discuss the molecular mechanisms that govern the crosstalk between systemic inflammation and neuroinflammation. In our view, inflammation spreading indicates a negative spiral between systemic diseases and AD. Therefore, "dampening inflammation" through the inhibition of cathepsin (Cat)B or CatS may be a novel therapeutic approach for delaying the onset of and enacting early intervention for AD..
7.	Hashioka S, Wu Z, Klegeris A., Glia-driven neuroinflammation and systemic inflammation in Alzheimer's disease., Curr Neuropharmacol ., doi: 10.2174/1570159X18666201111104509., 2020.11, The neuroinflammatory hypothesis of Alzheimer's disease (AD) was proposed more than 30 years ago. The involvement of the two main types of glial cells, microglia and astrocytes, in neuroinflammation was suggested early on. In this review we highlight that the exact contributions of reactive glia to AD pathogenesis remain difficult to define likely due to the heterogeneity of glia populations and alterations in their activation states through the stages of AD progression. In the case of microglia, it is becoming apparent that both beneficially and adversely activated cell populations can be identified at various stages of AD, which could be selectively targeted to either limit their damaging actions or enhance beneficial functions. In the case of astrocytes, less information is available about potential subpopulations of reactive cells; it also remains elusive whether astrocytes contribute to the neuropathology of AD by mainly gaining neurotoxic functions or losing their ability to support neurons due to astrocyte damage. We identify L-type calcium channel blocker, nimodipine, as a candidate drug for AD, which potentially targets both astrocytes and microglia. It has already shown consistent beneficial effects in basic experimental and clinical studies. We also highlight the recent evidence linking peripheral inflammation and neuroinflammation. Several chronic systemic inflammatory diseases, such as obesity, type 2 diabetes mellitus, and periodontitis, can cause immune priming or adverse activation of glia thus exacerbating neuroinflammation and increasing risk or facilitating progression of AD. Therefore, reducing peripheral inflammation is a potentially effective strategy for lowering AD prevalence..
8.	武　洲, 歯周病とアルツハイマー病型認知症, 保健の科学, 62（7）（特集・栄養・食事から認知症予防を考える）：p 459-462., 2020.06.
9.	武　洲, 歯周病感染がマクロファージにおけるアミロイドβの産生を引き起こす可能性（トピックス）, バイオサイエンスとインダストリー（B&I), 78(3),p234-235., 2020.06.
10.	Xu Yan;＠Zhou Wu;Biyao Wang;Tianhao Yu; Yue Hu; Sijian Wang;Chunfu Deng; Baohong Zhao; Hiroshi Nakanishi and Xinwen Zhan, Involvement of Cathepsins in Innate and Adaptive Immune Responses in Periodontitis, Evidence-Based Complementary and Alternative Medicine, doi.org/10.1155/2020/4517587, 2020.03, Periodontitis is an infectious disease whereby the chronic inflammatory process of the periodontium stimulated by bacterial products induces specific host cell responses. The activation of the host cell immune system upregulates the production of　inflammatorymediators,comprisingcytokinesandproteolyticenzymes,whichcontributetoinflammationandbonedestruction.Ithasbeenwellknownthatperiodontitisisrelatedtosystemicinflammationwhichlinkstonumeroussystemicdiseases,includingdiabetesandarteriosclerosis.Furthermore,periodontitishasbeenreportedinassociationwithneurodegenerativediseasessuchasAlzheimer’sdisease(AD)inthebrain.Regardingimmuneresponsesandinflammation,cathepsinB(CatB)playspivotalrolefortheinductionofIL-1β,cathepsinK-(CatK-)dependentactivetoll-likereceptor9(TLR9)signaling,andcathepsinS(CatS)which involves in regulating both TLR signaling and maturation of the MHC class II complex. Notably, both the production and proteolytic activities of cathepsins are upregulated in chronic inflammatory diseases, including periodontitis. In the present review, we focus on the roles of cathepsins in the innate and adaptive immune responses within periodontitis. We believe that　understandingtherolesofcathepsinsintheimmuneresponsesinperiodontitiswouldhelptoelucidatethetherapeuticstrategies of periodontitis, thus benefit for reduction of systemic diseases as well as neurodegenerative diseases in the global aging society..
11.	武　洲、中西　博, 歯周病のアルツハイマー病における関与メカニズム, 細胞, 50 (10): 45-49, 2018.06.
12.	武　洲、中西　博, 古くて新しいアルツハイマー病の脳炎症仮説と感染症仮説：鍵を握るミクログリアの老化と慢性的脳炎症, 日本薬理誌, 150、P1-7, 2017.06.
13.	武　洲、中西　博, 歯周病のアルツハイマー病における関与メカニズム：慢性全身性炎症からミクログリア活性化脳炎症へ, BIO Clinica , 32 (8): 75-80, 2017.06.
14.	Wu Z, Yu J, Zhu A, Nakanishi H, Nutrients, Microglia Aging, and Brain Aging, Oxid Med Cell Longev, 2016:7498528, 2016.06.

主要学会発表等

1.	武　洲, 口腔から認知症予防策を考える, 第38回保団連シンポジウム, 2023.10, 世界一の長寿国であるわが国では、高齢の認知症患者数が増加し続けている。2025年には高齢者の5人に1人、国民の17人に1人が認知症になると予測されている。認知症の 7 割を占めるアルツハイマー型認知症（Alzheimer's disease, AD）の 9 割は加齢に伴い発症し、20数年の長いスパンで進行する。一方、中高年者では口腔感染症である歯周病の有病率が6割を超え、加齢に連れ、症状が進行した人の割合も増える。AD患者に歯周病有病率が高い診療現場から「歯周病はADのリスクファクター」という仮説が提唱され、多くの臨床エビデンスにより支持されている。　さらに歯周病病原菌であるP.gingivalis 菌成分であるP.gingivalis LPSやgingipainがADの剖検脳に検出され、ADに歯周病の関与メカニズム解明が注目されるようになった。 AD脳病態の特徴として、アミロイド(A)の蓄積と形成される老人斑とタウの過剰リン酸化による神経原線維変化があるが、ミクログリアに依存する脳内炎症がAの蓄積、タウの過剰リン酸化を促進する。一方、全身炎症がミクログリアを活性化させ脳内炎症を誘発し慢性化させている。私たちは歯周病を慢性炎症と捉え、P.gingivalis菌とその成分のAD への関与メカニズムを解明し、日本からこのメカニズムを発信し続けている。これまでP.gingivalis菌とその成分が　１）AD 脳病態を誘発し促進する　２）全身炎症を増大させる　３）全身でA産生を誘導する　４）全身のを脳内輸入させるように、多方向的にADの誘発と進行に関わることが明らかになっている。本シンポジウムでは.gingivalis菌のADへの関与について、私たちが得られた知見を踏まえて解説するとともに、全身炎症の介入することにより、認知機能の改善効果も紹介する。 2019（令和元）年6月に策定された「認知症施策推進大綱」に、｢共生｣と｢予防｣を車の両輪として、この施策を推進すると公表しており、その「予防」を「認知症にならない」ではなく、「認知症になるのを遅らせる」、「認知症になっても進行を緩やかにする」と定義し、具体的に70 歳代での発症を 10 年間で１歳遅らせることを目標と挙げている。ADが発症してから根本的な治療法がない現状の中、治療と予防の可能な口腔感染症ならびに全身炎症を減らすことが、ADの発症と進行を遅らせる認知症予防対策として提案したい。.
2.	武　洲, 口腔から考える認知症予防, 第23回日本抗加齢医学会総会, 2023.06, [URL], 地球規模の高齢人口増加に伴い、世界の認知症患者は 2050年には1 億 3千万人を突破すると推計されている。高齢化率世界一の我が国では2025年には高齢者の3人に1人が認知症とその予備軍になると見込まれる「2025年問題」に直面している。認知症の 7 割を占めるアルツハイマー型認知症（Alzheimer's disease, AD）の 9 割は加齢に伴い発症し、ADの脳病態にはアミロイドβ蓄積による老人班、Tau蛋白質過剰リン酸化による神経原線維変性ならびにミクログリア活性化に伴う脳内炎症がある。 糖尿病やリウマチ関節炎など全身炎症性疾患はADの発症と病態進行に関与し、口腔慢性炎症の歯周病は糖尿病やリウマチ関節炎を促す。一方、歯周病は高齢者ならびにAD患者における認知機能低下と正相関し、歯周病病原菌のP.gingvalis菌に由来するlipopolysaccharide（P.gLPS）などの成分がAD剖検脳にも検出されていることから、口腔と認知症への関与が注目されている。私たちは長年にわたり炎症のADへ関与するメカニズムを追究し続けて明らかにしたADの誘発と増悪因子を対象にした認知症予防開発も行っている。 ADは20数年の長いスパンで進行するが、私たちはこれまでP.gingvalis菌が年齢に依存した １）AD脳病態を誘発し促進すること、２）全身炎症を増大させること、３）脳外でアミロイドβ産生を誘導すること、４）脳外アミロイドβを脳内に輸入させることを明らかにしてきた。本シンポジウムでは口腔から多方向にADの発症と進行に関与するメカニズムを解説し、炎症を対象とした認知症の予防開発も紹介する。 炎症は細胞レベルの老化を促進する観点から、口腔より「炎症軽減」することで細胞レベル抗老化効果を得ることができる。抗加齢的な視点から、口腔より「炎症制御」をすることで加齢につれて増加する認知症の発症と進行を遅らせる現実的な予防アプローチとして提案したい。 .
3.	武　洲, 認知症を口から防ぐ〜口腔ブレインサイエンス〜 , 国際医科学研究会 第20回フォーラム, 2022.06.
4.	武　洲, 口腔感染症と認知症：関連メカニズムから予防策を考える, 第30回日本病態生理学会大会, 2022.01.
5.	武　洲, 歯周病がアルツハイマー型認知症に関与するメカニズム, 認知症と口腔機能研究会 JRSDOF 第２回学術集会, 2021.08.
6.	Zhou WU, The involvement mechanism of P. gingivalis infection in Alzheimer disease　, SNU – KYUSHU JOINT SYMPOSIUM, 2021.06.
7.	武　洲　, 全身炎症によるミクログリア活性化とアルツハイマー病, 116回日本精神神経学会学術総会, 2020.09.
8.	武　洲, 口腔からアルツハイマー型認知症を考える, 第42回九州口腔衛生学会総会, 2020.09.
9.	Yebo Gu, Junjun Ni, Zhou Wu, Ichiro Takahashi, Chronic systemic exposure of Lipopolysaccharide from Porphyromonas gingivalis induces memory decline through the upregulation of the bone loss promotion molecule IL-17 in middle-aged mice, 第72回日本薬理学会西南部会, 2019.11.
10.	Yebo Gu, Junjun Ni, Zhou Wu, Ichiro Takahashi, Chronic systemic exposure of PgLPS induces long bone loss and cognitive decline in middle-aged mice, 第78回日本矯正歯科学会, 2019.11.
11.	Yebo Gu, Junjun Ni, Muzhou Jiang, Zhou Wu, Ichiro Takahashi, Chronic systemic exposure of Lipopolysaccharide from Porphyromonas gingivalis induces Memory decline and Bone loss in Middle-aged Mice, 6th Congress of ASCNP, 2019.10.
12.	Fan Zeng, Junjun Ni, Zhou Wu , Porphyromonas gingivalis infection increases RAGE production in hCMEC/D3 cell line, 6th Congress of ASCNP, 2019.10.
13.	Wanyi Huang, Junjun Ni, Zhou Wu,, Porphyromonas gingivalis infected Leptomeningeal Cells Reduces Synapses Proteins in Primary Cultured Neurons, 6th Congress of AsCNP, 2019.10.
14.	Muzhou Jiang, Junjun Ni, Yebo Gu, Zhou Wu, Microglia induces tau hyperphosphorylation of cultured neurons after exposure to Porphyromonas gingivalis LPS, 6th Congress of ASCNP, 2019.10.
15.	Zhou WU, Inflammation and Lysosomal Enzymes: Prevention Approach of Cognitive Decline, Neurology Conference , 2019.06.
16.	黄婉怡,　倪軍軍，武洲, The transduce effect of leptomeningeal cells in peripheral exposure of Porphyromonas gingivalis induced neurodegeneration in Alzheimer’s disease., 第92回日本薬理学会年会, 2019.03.
17.	顧也博，倪軍軍，姜慕舟，武洲，高橋一郎, Porphyromonas gingivalis由来LPSによる中年マウスおける記憶低下ならびに骨量減少の誘発, 第92回日本薬理学会年会, 2019.03.
18.	曽　凡, 倪　軍軍，武　洲, Porphyromonas gingivalis感染による内皮細胞におけるRAGE発現が増加させる, 第92回日本薬理学会年会, 2019.03.
19.	孟　ジエ, 朱　愛琴，倪　軍軍，林　良憲，中西　博，武　洲, 酸化ストレス誘発されるニューロン障害およびミクログリア依存性脳炎症に対するRatanasampilの抑制作用, 第92回日本薬理学会年会 , 2019.03.
20.	姜慕舟，倪軍軍，武洲, ブラジル産プロポリスは低酸素によるミクログリア依存性脳炎症反応を抑制する, 第92回日本薬理学会年会, 2019.03.
21.	武　洲, ジンジバリス菌とアルツハイマー病, 「Hindgut Club Japan」シンポジウム, 2018.12.
22.	武　洲, ジンジバリス菌とアルツハイマー病, 第60回歯科基礎医学会学術大会, 2018.09.
23.	Ran Nie, Junjun Ni, Yoshinori Hayashi, Zhou Wu, Yanmin Zhou, 慢性全身性Porphyromonas gingivalis感染に伴う全身性アミロイドβ代謝におけるマクロファージの関与, 第60回歯科基礎医学会学術大会, 2018.09.
24.	Yebo Gu, Junjun Ni, Zhou Wu, Ichiro Takahashi, Porphyromonas gingivalis由来LPSの慢性投与は中年モウスにおける骨量低下ならびに記憶低下を誘発する, 第60回歯科基礎医学会学術大会, 2018.09.
25.	Jie Meng, Junjun Ni, Yoshinori Hayashi, Hiroshi Nakanishi, Aiqin Zhu　and Zhou Wu, チベット薬Ratanasampilは、低酸素によるミクログリアにおける酸化ストレスならびにNF-κB活性化に依存した炎症反応を抑制する, 第60回歯科基礎医学会学術大会, 2018.09.
26.	Zhu A, Ni J, Meng J, Nakanishi H ,Wu Z, ブラジル産グリーンプロポリスは、チベット高原に住む高齢者の全身炎症を軽減して認知機能の低下を防ぐ, 第60回歯科基礎医学会学術大会, 2018.09.
27.	武　洲, 口腔健康の高齢社会への貢献　深圳歯科教育プログラム, 深圳歯科教育プログラム, 2018.06.
28.	Wu Z, Cathepsin B, novel therapeutic target for microglia-mediated neuroinflammation, special seminar in University of Southampton, 2017.02.
29.	武　洲, 歯周病菌感染による脳内アルツハイマー様病態の誘発メカニズム, 第58回歯科基礎医学会学術大会・サテライトシンポジウム, 2016.08.
30.	Hiro Take, Oral health and healthy life expectancy, The 1st International Symposium for Women Researchers on Advanced Science and Technology conjugated with Seminar for Young Researchers, 2016.07.
31.	Hiro Take, Oral health, Nutrition and healthy life expectancy, 9th CASPN, 2015.05.

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