| 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. |
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. |
| 5. |
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.. |
| 6. |
Wu Z, Yu J, Zhu A, Nakanishi H, Nutrients, Microglia Aging, and Brain Aging, Oxid Med Cell Longev, 2016:7498528, 2016.06. |
| 7. |
Wu Z, Hiroshi Nakanishi, Lessons from Microglia Aging for the Link between Inflammatory Bone Disorders and Alzheimer's Disease., J Immunol Res, 2015.05. |
| 8. |
Wu Z, Hiroshi Nakanishi, Connection between periodontitis and Alzheimer's disease: possible roles of microglia and leptomeningeal cells, J Pharmacol Sci., 2014.08. |
| 9. |
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. |
| 10. |
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. |
| 11. |
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. |
| 12. |
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. |
