| 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, 歯周病菌が認知症に与える影響, デンタルダイアモンド誌, 2021.04. |
| 6. |
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。. |
| 7. |
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.. |
| 8. |
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.. |
| 9. |
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. |
| 10. |
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. |
| 11. |
Hiroshi Nakanishi , Saori Nonaka , ＠Zhou Wu., Microglial cathepsin B and Porphyromonas gingivalis gingipains as potential therapeutic targets for sporadic Alzheimer's disease., CNS Neurol Disord Drug Targets., 10.2174/1871527319666200708125130, Online ahead of print., 2020.07. |
| 12. |
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.. |
| 13. |
武 洲, 歯周病とアルツハイマー型認知症, 保健の科学, 2020.07. |
| 14. |
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. |
| 15. |
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. |
| 16. |
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. |
| 17. |
Wu Z, Yu J, Zhu A, Nakanishi H, Nutrients, Microglia Aging, and Brain Aging, Oxid Med Cell Longev, 2016:7498528, 2016.06. |
| 18. |
Wu Z, Hiroshi Nakanishi, Lessons from Microglia Aging for the Link between Inflammatory Bone Disorders and Alzheimer's Disease., J Immunol Res, 2015.05. |
| 19. |
Wu Z, Hiroshi Nakanishi, Connection between periodontitis and Alzheimer's disease: possible roles of microglia and leptomeningeal cells, J Pharmacol Sci., 2014.08. |
| 20. |
Wu Z, Zhu A, Wu S, Hiroshi Nakanishi, Preventing and Reversing “Microglia-Aging” by Nature Elements for Slow Brain- Aging , J Neurological Disorders. 2013 2：1：1000143, 2013.12. |
| 21. |
Hiroshi Nakanishi, Yoshinori Hayashi, Wu Z, The role of microglial mtDNA damage in age-dependent prolonged LPS-induced sickness behavior., Neuron Glia Biol. 216:133-42, 2011.02. |
| 22. |
Nakanishi H. and Wu Z. , Microglia-aging: Roles of microglial
lysosome- and mitochondria-deroved reactive oxygen species in brain aging. Behav. Brain Res.
, Behav. Brain Res. Behav Brain Res., 19; 201(1):1-7., 2009.07. |
| 23. |
Wu Z, Nakanishi H. , Phosphatidylserine-containing liposomes: potential pharmacological interventions against inflammatory and immune diseases through the production of prostaglandin E(2) after uptake by myeloid derived phagocytes., Arch Immunol Ther Exp , 2011.01. |
