學術產出-Theses
Article View/Open
Publication Export
-
題名 新型抗發炎硫脲小分子藥物能改善微膠質細胞因β-澱粉樣蛋白所引起之粒線體功能缺失
A novel thiourea possessing anti-inflammatory property rescues Aβ-induced mitochondrial dysfunction in microglia作者 孫儀馨
Sun, Yi-Sin貢獻者 詹銘煥
孫儀馨
Sun, Yi-Sin關鍵詞 阿茲海默氏症
微膠質細胞
β-澱粉樣蛋白
粒線體
生物能量
硫脲
Alzheimer’s disease
Microglia
Beta-amyloid
Mitochondria
Bioenergetics
Thiourea日期 2018 上傳時間 1-Oct-2018 12:12:04 (UTC+8) 摘要 阿茲海默氏症 (Alzheimer’s disease) 是一種常見的神經退化性疾病，其特徵為大腦中神經細胞漸進性的損傷以及微膠質細胞的過度活化。除此之外，β-澱粉樣蛋白 (Aβ) 的堆積是阿茲海默氏症中重要的病理特徵，並在疾病的發展中扮演重要的角色。由於β-澱粉樣蛋白的製造與清除失衡，使得β-澱粉樣蛋白產生堆積。而過多的β-澱粉樣蛋白會過度活化微膠質細胞，也會引發神經細胞之粒線體功能缺陷。病理過程造成慢性神經性發言及神經性退化的後果，最終導致神經元死亡。然而，β-澱粉樣蛋白對於微膠質細胞之粒線體的影響以及相關機制，卻較少被探討。因此，我們假設β-澱粉樣蛋白會引起微膠質細胞中粒線體功能的損傷，並間接影響微膠質細胞所調控的免疫發炎反應。本研究將微膠質細胞暴露在β-澱粉樣蛋白下，並檢測其粒線體的功能，包含生物能量（bioenergetics）、粒線體形態，以及相關訊號傳遞路徑的變化。此外，一個新型硫脲小分子藥物＃326，由於具有抗發炎能力，因此本篇研究進一步測試＃326是否能透過抗發炎的反應，來挽救受到β-澱粉樣蛋白所導致的粒線體功能缺失。本篇研究結果顯示，β-澱粉樣蛋白會降低粒線體的生物能量及改變粒線體形態與分佈，造成微膠質細胞中粒線體的功能損害。此外，β-澱粉樣蛋白會促進微膠質細胞中ERK的磷酸化。然而，在β-澱粉樣蛋白的作用下，#326不僅能挽救粒線體的功能缺失，並能降低β-澱粉樣蛋白引發之ERK過度磷酸化。據此推斷，#326可能透過調解ERK的訊號傳遞路徑，改善β-澱粉樣蛋白引起的線粒體失能。總結以上，我們的研究結果顯示#326能改善β-澱粉樣蛋白對微膠質細胞中線粒體功能的損害，而這種粒線體保護功能，可能與其調解ERK1/2的過度磷酸化作用有關。此外，透過研究新型的硫脲小分子藥物#326的作用機制，或許能得到阿茲海默氏症病理研究的相關線索，甚至對神經退化性疾病的藥物治療發展中有所幫助。
Alzheimer’s disease (AD), a neurodegenerative disease, is characterized by the progressive neuronal loss and overactive microglia. Besides, amyloid-β (Aβ) is a histopathological hallmark in AD, which plays a crucial role in the pathogenesis of this disease. The imbalance between Aβ production and clearance leads to the accumulation of Aβ in extracellular and intracellular compartments. Growing evidence suggests that excessive amyloid-β (Aβ) accumulation instigates early deficits in mitochondrial function and causes a self-propelling degeneration cycle which sustains chronic neuroinflammation induced by microglial and eventually lead to neuronal damages. Nevertheless, how Aβ affects mitochondrial function in microglia is still elusive. In this study, it was hypothesized that Aβ would cause mitochondrial defects in microglia and further exacerbate microglial activation which is the causation of neuronal inflammation in AD.To investigate this premise, mitochondrial function, including mitochondrial bioenergetics, mitochondrial morphology, and mitochondrial relative pathway were tested in microglial cells challenged with Aβ. In addition, the protective effects of a novel thiourea, compound #326, which possesses anti-inflammatory effect were also been examined in this study. Our data indicated that Aβ impaired mitochondrial function as evidenced by the decreased bioenergetics, fragmented mitochondria, and abnormal distribution. In addition, our results also showed the activation of extracellular-signal regulated kinase (ERK) phosphorylation under Aβ stimulation. Intriguingly, our data indicated that the rescuing effects of the novel compound on the aberrant bioenergetics elicited by Aβ are involved in the modulation of ERK activity that is highly associated with mitochondrial damages under the circumstances of Aβ toxicity. Therefore, studying the mechanism of the new thiourea, compound #326, may provide the clues to study the pathology of AD, and even improve the design of pharmacological intervention for AD.參考文獻 Association, A. s. (2018). 2018 Alzheimer`s disease facts and figures. Alzheimer`s & Dementia, 14(3), 367-429.Ballweg, K., Mutze, K., Königshoff, M., Eickelberg, O., & Meiners, S. (2014). Cigarette smoke extract affects mitochondrial function in alveolar epithelial cells. American Journal of Physiology-Lung Cellular and Molecular Physiology, 307(11), L895-L907.Baloyannis, S. J. (2006). Mitochondrial alterations in Alzheimer`s disease. Journal of Alzheimer`s Disease, 9(2), 119-126.Bernhart, E., Kollroser, M., Rechberger, G., Reicher, H., Heinemann, A., Schratl, P., . . . DeVaney, T. (2010). Lysophosphatidic acid receptor activation affects the C13NJ microglia cell line proteome leading to alterations in glycolysis, motility, and cytoskeletal architecture. Proteomics, 10(1), 141-158.Berridge, M. J. (2013). Dysregulation of neural calcium signaling in Alzheimer disease, bipolar disorder and schizophrenia. Prion, 7(1), 2-13.Blass, J. P., Sheu, R. K., & Gibson, G. E. (2000). Inherent abnormalities in energy metabolism in Alzheimer disease. Interaction with cerebrovascular compromise. Ann N Y Acad Sci, 903, 204-221.Brand, M. D., & Nicholls, D. G. (2011). Assessing mitochondrial dysfunction in cells. Biochemical Journal, 435(2), 297-312.Cabezas-Opazo, F. A., Vergara-Pulgar, K., Pérez, M. J., Jara, C., Osorio-Fuentealba, C., & Quintanilla, R. A. (2015). Mitochondrial dysfunction contributes to the pathogenesis of Alzheimer’s disease. Oxidative medicine and cellular longevity, 2015.Cabezas-Opazo, F. A., Vergara-Pulgar, K., Perez, M. J., Jara, C., Osorio-Fuentealba, C., & Quintanilla, R. A. (2015). Mitochondrial Dysfunction Contributes to the Pathogenesis of Alzheimer`s Disease. Oxid Med Cell Longev, 2015, 509654. doi:10.1155/2015/509654Cai, Z., Hussain, M. D., & Yan, L.-J. (2014). Microglia, neuroinflammation, and beta-amyloid protein in Alzheimer`s disease. International Journal of Neuroscience, 124(5), 307-321.Chacko, B. K., Kramer, P. A., Ravi, S., Benavides, G. A., Mitchell, T., Dranka, B. P., . . . Bailey, S. M. (2014). The Bioenergetic Health Index: a new concept in mitochondrial translational research. Clinical science, 127(6), 367-373.Chénais, B., Morjani, H., & Drapier, J. C. (2002). Impact of endogenous nitric oxide on microglial cell energy metabolism and labile iron pool. Journal of neurochemistry, 81(3), 615-623.Chern, J.-H., Hsu, P.-C., Wang, L.-W., Tsay, H.-J., Kang, I.-J., & Shie, F.-S. (2010). Modulation of microglial immune responses by a novel thiourea derivative. Chemico-biological interactions, 188(1), 228-236.Chow, V. W., Mattson, M. P., Wong, P. C., & Gleichmann, M. (2010). An overview of APP processing enzymes and products. Neuromolecular medicine, 12(1), 1-12.Condello, C., Yuan, P., & Grutzendler, J. (2017). Microglia-mediated neuroprotection, TREM2 and Alzheimer’s disease: Evidence from Optical Imaging. Biological psychiatry.Cuello, A. C. (2005). Intracellular and extracellular Aβ, a tale of two neuropathologies. Brain Pathology, 15(1), 66-71.Cummings, J. L., Morstorf, T., & Zhong, K. (2014). Alzheimer’s disease drug-development pipeline: few candidates, frequent failures. Alzheimer`s Research & Therapy, 6(4), 37. doi:10.1186/alzrt269De Felice, F. G., & Ferreira, S. T. (2014). Inflammation, defective insulin signaling, and mitochondrial dysfunction as common molecular denominators connecting type 2 diabetes to Alzheimer disease. Diabetes, DB_131954.Dranka, B. P., Hill, B. G., & Darley-Usmar, V. M. (2010). Mitochondrial reserve capacity in endothelial cells: The impact of nitric oxide and reactive oxygen species. Free Radic Biol Med, 48(7), 905-914. doi:10.1016/j.freeradbiomed.2010.01.015Du, H., Guo, L., Yan, S., Sosunov, A. A., McKhann, G. M., & Yan, S. S. (2010). Early deficits in synaptic mitochondria in an Alzheimer`s disease mouse model. Proceedings of the National Academy of Sciences, 201006586.Fu, W., Vukojevic, V., Patel, A., Soudy, R., MacTavish, D., Westaway, D., . . . Jhamandas, J. (2017). Role of microglial amylin receptors in mediating beta amyloid (Aβ)-induced inflammation. Journal of neuroinflammation, 14(1), 199.Galloway, C. A., Lee, H., & Yoon, Y. (2012). Mitochondrial morphology—emerging role in bioenergetics. Free Radical Biology and Medicine, 53(12), 2218-2228.Gupta, K. J., Igamberdiev, A. U., & Mur, L. A. (2012). NO and ROS homeostasis in mitochondria: a central role for alternative oxidase. New Phytologist, 195(1), 1-3.Hay, S. I., Abajobir, A. A., Abate, K. H., Abbafati, C., Abbas, K. M., Abd-Allah, F., . . . Abera, S. F. (2017). Global, regional, and national disability-adjusted life-years (DALYs) for 333 diseases and injuries and healthy life expectancy (HALE) for 195 countries and territories, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. The Lancet, 390(10100), 1260-1344.Hayashi, Y., Morinaga, S., Zhang, J., Satoh, Y., Meredith, A. L., Nakata, T., ... & Nakanishi, H. (2016). BK channels in microglia are required for morphine-induced hyperalgesia. Nature communications, 7, 11697.Hirai, K., Aliev, G., Nunomura, A., Fujioka, H., Russell, R. L., Atwood, C. S., . . . Tabaton, M. (2001). Mitochondrial abnormalities in Alzheimer`s disease. Journal of Neuroscience, 21(9), 3017-3023.Huang, Z., Zhou, T., Sun, X., Zheng, Y., Cheng, B., Li, M., . . . He, C. (2017). Necroptosis in microglia contributes to neuroinflammation and retinal degeneration through TLR4 activation. Cell Death And Differentiation, 25, 180. doi:10.1038/cdd.2017.141https://www.nature.com/articles/cdd2017141#supplementary-informationHuang, Z., Zhou, T., Sun, X., Zheng, Y., Cheng, B., Li, M., . . . He, C. (2018). Necroptosis in microglia contributes to neuroinflammation and retinal degeneration through TLR4 activation. Cell death and differentiation, 25(1), 180.Itoh, K., Nakamura, K., Iijima, M., & Sesaki, H. (2013). Mitochondrial dynamics in neurodegeneration. Trends Cell Biol, 23(2), 64-71. doi:10.1016/j.tcb.2012.10.006Ježek, P., & Hlavatá, L. (2005). Mitochondria in homeostasis of reactive oxygen species in cell, tissues, and organism. The international journal of biochemistry & cell biology, 37(12), 2478-2503.Kashatus, J. A., Nascimento, A., Myers, L. J., Sher, A., Byrne, F. L., Hoehn, K. L., . . . Kashatus, D. F. (2015). Erk2 phosphorylation of Drp1 promotes mitochondrial fission and MAPK-driven tumor growth. Molecular cell, 57(3), 537-551.Kim, B., Park, J., Chang, K.-T., & Lee, D.-S. (2016). Peroxiredoxin 5 prevents amyloid-beta oligomer-induced neuronal cell death by inhibiting ERK–Drp1-mediated mitochondrial fragmentation. Free Radical Biology and Medicine, 90, 184-194.Kim, D. I., Lee, K. H., Oh, J. Y., Kim, J. S., & Han, H. J. (2017). Relationship Between beta-Amyloid and Mitochondrial Dynamics. Cell Mol Neurobiol, 37(6), 955-968. doi:10.1007/s10571-016-0434-4Kitamura, Y., Shimohama, S., Ota, T., Matsuoka, Y., Nomura, Y., & Taniguchi, T. (1997). Alteration of transcription factors NF-κB and STAT1 in Alzheimer`s disease brains. Neuroscience letters, 237(1), 17-20.Kogot-Levin, A., Saada, A., Leibowitz, G., Soiferman, D., Douiev, L., Raz, I., & Weksler-Zangen, S. (2016). Upregulation of Mitochondrial Content in Cytochrome c Oxidase Deficient Fibroblasts. PLoS ONE, 11(10), e0165417. doi:10.1371/journal.pone.0165417Kreutzberg, G. W. (1996). Microglia: a sensor for pathological events in the CNS. Trends in neurosciences, 19(8), 312-318.Langley, M., Ghosh, A., Charli, A., Sarkar, S., Ay, M., Luo, J., . . . Jin, H. (2017). Mito-apocynin prevents mitochondrial dysfunction, microglial activation, oxidative damage, and progressive neurodegeneration in mitopark transgenic mice. Antioxidants & redox signaling, 27(14), 1048-1066.Li, C., Yang, F., Liu, F., Li, D., & Yang, T. (2018). NRF2/HO-1 activation via ERK pathway involved in the anti-neuroinflammatory effect of Astragaloside IV in LPS induced microglial cells. Neuroscience letters, 666, 104-110.Li, M., Chen, L., Lee, D. H. S., Yu, L.-C., & Zhang, Y. (2007). The role of intracellular amyloid β in Alzheimer`s disease. Progress in neurobiology, 83(3), 131-139.Logsdon, R. G., Gibbons, L. E., McCurry, S. M., & Teri, L. (1999). Quality of life in Alzheimer`s disease: patient and caregiver reports. Journal of Mental health and Aging, 5, 21-32.Lu, R., Lukowski, R., Sausbier, M., Zhang, D. D., Sisignano, M., Schuh, C. D., ... &. Schmidtko, A. (2014). BK Ca channels expressed in sensory neurons modulate inflammatory pain in mice. PAIN®, 155(3), 556-565.Lyck, L., Santamaria, I. D., Pakkenberg, B., Chemnitz, J., Schrøder, H. D., Finsen, B., & Gundersen, H. J. G. (2009). An empirical analysis of the precision of estimating the numbers of neurons and glia in human neocortex using a fractionator-design with sub-sampling. Journal of neuroscience methods, 182(2), 143-156.Manczak, M., Calkins, M. J., & Reddy, P. H. (2011). Impaired mitochondrial dynamics and abnormal interaction of amyloid beta with mitochondrial protein Drp1 in neurons from patients with Alzheimer`s disease: implications for neuronal damage. Human molecular genetics, 20(13), 2495-2509.Miklossy, J., Kis, A., Radenovic, A., Miller, L., Forro, L., Martins, R., . . . Mihaly, L. (2006). Beta-amyloid deposition and Alzheimer`s type changes induced by Borrelia spirochetes. Neurobiology of aging, 27(2), 228-236.Morales, I., Guzmán-Martínez, L., Cerda-Troncoso, C., Farías, G. A., & Maccioni, R. B. (2014). Neuroinflammation in the pathogenesis of Alzheimer’s disease. A rational framework for the search of novel therapeutic approaches. Frontiers in cellular neuroscience, 8, 112.Moreira, P., Cardoso, S., Santos, M., & Oliveira, C. (2006). The key role of mitochondria in Alzheimer`s disease. Journal of Alzheimer`s Disease, 9(2), 101-110.Moreira, P. I., Carvalho, C., Zhu, X., Smith, M. A., & Perry, G. (2010). Mitochondrial dysfunction is a trigger of Alzheimer`s disease pathophysiology. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 1802(1), 2-10. doi:https://doi.org/10.1016/j.bbadis.2009.10.006Morkuniene, R., Cizas, P., Jankeviciute, S., Petrolis, R., Arandarcikaite, O., Krisciukaitis, A., & Borutaite, V. (2015). Small Aβ1–42 oligomer‐induced membrane depolarization of neuronal and microglial cells: Role of N‐methyl‐D‐aspartate receptors. Journal of neuroscience research, 93(3), 475-486.Morris, G. P., Clark, I. A., Zinn, R., & Vissel, B. (2013). Microglia: a new frontier for synaptic plasticity, learning and memory, and neurodegenerative disease research. Neurobiology of learning and memory, 105, 40-53.Morris, J. C. (2012). Revised criteria for mild cognitive impairment may compromise the diagnosis of Alzheimer disease dementia. Archives of neurology, 69(6), 700-708.Moss, D. W., & Bates, T. E. (2001). Activation of murine microglial cell lines by lipopolysaccharide and interferon‐γ causes NO‐mediated decreases in mitochondrial and cellular function. European Journal of Neuroscience, 13(3), 529-538.Nakajima, K., & Kohsaka, S. (2004). Microglia: neuroprotective and neurotrophic cells in the central nervous system. Curr Drug Targets Cardiovasc Haematol Disord, 4(1), 65-84.Onyango, I. G. (2018). Modulation of mitochondrial bioenergetics as a therapeutic strategy in Alzheimer`s disease. Neural Regen Res, 13(1), 19-25. doi:10.4103/1673-5374.224362Onyango, I. G., Dennis, J., & Khan, S. M. (2016). Mitochondrial dysfunction in Alzheimer’s disease and the rationale for bioenergetics based therapies. Aging and disease, 7(2), 201.Orihuela, R., McPherson, C. A., & Harry, G. J. (2016). Microglial M1/M2 polarization and metabolic states. British journal of pharmacology, 173(4), 649-665.Palacino, J. J., Sagi, D., Goldberg, M. S., Krauss, S., Motz, C., Wacker, M., . . . Shen, J. (2004). Mitochondrial dysfunction and oxidative damage in parkin-deficient mice. J Biol Chem, 279(18), 18614-18622. doi:10.1074/jbc.M401135200Park, J., Min, J.-S., Kim, B., Chae, U.-B., Yun, J. W., Choi, M.-S., . . . Lee, D.-S. (2015). Mitochondrial ROS govern the LPS-induced pro-inflammatory response in microglia cells by regulating MAPK and NF-κB pathways. Neuroscience letters, 584, 191-196.Park, L. C., Zhang, H., Sheu, K. F. R., Calingasan, N. Y., Kristal, B. S., Gordon Lindsay, J., & Gibson, G. E. (1999). Metabolic impairment induces oxidative stress, compromises inflammatory responses, and inactivates a key mitochondrial enzyme in microglia. Journal of neurochemistry, 72(5), 1948-1958.Pérez, M. J., Jara, C., Muñoz‐Urrutia, E., & Quintanilla, R. A. (2016). New Targets for Diagnosis and Treatment Against Alzheimer’s Disease: The Mitochondrial Approach Update on Dementia: InTech.Perry, C. G., Kane, D. A., Lanza, I. R., & Neufer, P. D. (2013). Methods for assessing mitochondrial function in diabetes. Diabetes, 62(4), 1041-1053. doi:10.2337/db12-1219Picard, M., Shirihai, O. S., Gentil, B. J., & Burelle, Y. (2013). Mitochondrial morphology. transitions and functions: implications for retrograde signaling?. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 304(6), R393-R406.Pinho, C. M., Teixeira, P. F., & Glaser, E. (2014). Mitochondrial import and degradation of amyloid-β peptide. Biochimica et Biophysica Acta (BBA)-Bioenergetics, 1837(7), 1069-1074.Pouysségur, J., & Lenormand, P. (2016). ERK1 and ERK2 map kinases: specific roles or functional redundancy? Frontiers in cell and developmental biology, 4, 53.Qi, X., Qvit, N., Su, Y. C., & Mochly-Rosen, D. (2013). A novel Drp1 inhibitor diminishes aberrant mitochondrial fission and neurotoxicity. J Cell Sci, 126(Pt 3), 789-802. doi:10.1242/jcs.114439Rambold, A. S., & Pearce, E. L. (2017). Mitochondrial dynamics at the interface of immune cell metabolism and function. Trends in immunology.Ransohoff, R. M. (2016). A polarizing question: do M1 and M2 microglia exist? Nature neuroscience, 19(8), 987.Reemst, K., Noctor, S. C., Lucassen, P. J., & Hol, E. M. (2016). The indispensable roles of microglia and astrocytes during brain development. Frontiers in human neuroscience, 10, 566.Sangiuliano, B., Pérez, N. M., Moreira, D. F., & Belizário, J. E. (2014). Cell death-associated. molecular-pattern molecules: inflammatory signaling and control. Mediators of inflammation, 2014.Sarkar, S., Malovic, E., Harishchandra, D. S., Ghaisas, S., Panicker, N., Charli, A., . . . Anantharam, V. (2017). Mitochondrial impairment in microglia amplifies NLRP3 inflammasome proinflammatory signaling in cell culture and animal models of Parkinson’s disease. NPJ Parkinson`s disease, 3(1), 30.Sarlus, H., & Heneka, M. T. (2017). Microglia in Alzheimer’s disease. The Journal of clinical investigation, 127(9), 3240-3249.Schilling, T., Stock, C., Schwab, A., & Eder, C. (2004). Functional importance of Ca2+‐activated K+ channels for lysophosphatidic acid‐induced microglial migration. European Journal of Neuroscience, 19(6), 1469-1474.Sengupta, U., Nilson, A. N., & Kayed, R. (2016). The role of amyloid-β oligomers in toxicity, propagation, and immunotherapy. EBioMedicine, 6, 42-49.Shie, F. S., Breyer, R. M., & Montine, T. J. (2005). Microglia Lacking E Prostanoid Receptor Subtype 2 Have Enhanced Aβ Phagocytosis yet Lack Aβ-Activated Neurotoxicity. Am J Pathol, 166(4), 1163-1172.Shirendeb, U., Reddy, A. P., Manczak, M., Calkins, M. J., Mao, P., Tagle, D. A., & Hemachandra Reddy, P. (2011). Abnormal mitochondrial dynamics, mitochondrial loss and mutant huntingtin oligomers in Huntington`s disease: implications for selective neuronal damage. Human molecular genetics, 20(7), 1438-1455.Smith, R. A., Hartley, R. C., Cocheme, H. M., & Murphy, M. P. (2012). Mitochondrial pharmacology. Trends in pharmacological sciences, 33(6), 341-352.Son, J. M., Sarsour, E. H., Kakkerla Balaraju, A., Fussell, J., Kalen, A. L., Wagner, B. A., . . . Goswami, P. C. (2017). Mitofusin 1 and optic atrophy 1 shift metabolism to mitochondrial respiration during aging. Aging cell, 16(5), 1136-1145.Spuch, C., Ortolano, S., & Navarro, C. (2012). New insights in the amyloid-Beta interaction with mitochondria. Journal of aging research, 2012.Standridge, J. B. (2006). Vicious cycles within the neuropathophysiologic mechanisms of Alzheimer`s disease. Current Alzheimer Research, 3(2), 95-107.Swerdlow, R. H. (2017). Mitochondria and mitochondrial cascades in Alzheimer’s disease. Journal of Alzheimer`s Disease(Preprint), 1-14.Tammineni, P., Jeong, Y. Y., Feng, T., Aikal, D., & Cai, Q. (2017). Impaired axonal retrograde trafficking of the retromer complex augments lysosomal deficits in Alzheimer’s disease neurons. Human molecular genetics, 26(22), 4352-4366.Tanhehco, E. J. (2001). Potassium channel modulators as anti-inflammatory agents. Expert Opinion on Therapeutic Patents, 11(7), 1137-1145. doi:10.1517/13543776.11.7.1137Trevisan, T., Pendin, D., Montagna, A., Bova, S., Ghelli, A. M., & Daga, A. (2018). Manipulation of Mitochondria Dynamics Reveals Separate Roles for Form and Function in Mitochondria Distribution. Cell reports, 23(6), 1742-1753.Trimmer, P. A., & Borland, M. K. (2005). Differentiated Alzheimer`s disease transmitochondrial cybrid cell lines exhibit reduced organelle movement. Antioxidants & redox signaling, 7(9-10), 1101-1109.Urrutia, P. J., Mena, N. P., & Nunez, M. T. (2014). The interplay between iron accumulation, mitochondrial dysfunction, and inflammation during the execution step of neurodegenerative disorders. Frontiers in pharmacology, 5, 38.Valente, A. J., Maddalena, L. A., Robb, E. L., Moradi, F., & Stuart, J. A. (2017). A simple ImageJ macro tool for analyzing mitochondrial network morphology in mammalian cell culture. Acta histochemica, 119(3), 315-326.Velliquette, R. A., O`Connor, T., & Vassar, R. (2005). Energy inhibition elevates β-secretase levels and activity and is potentially amyloidogenic in APP transgenic mice: possible early events in Alzheimer`s disease pathogenesis. Journal of Neuroscience, 25(47), 10874-10883.Von Bernhardi, R., Eugenín-von Bernhardi, L., & Eugenín, J. (2015). Microglial cell dysregulation in brain aging and neurodegeneration. Frontiers in aging neuroscience, 7, 124.Wang, W.-Y., Tan, M.-S., Yu, J.-T., & Tan, L. (2015). Role of pro-inflammatory cytokines released from microglia in Alzheimer’s disease. Annals of translational medicine, 3(10).Wang, X., Su, B., Fujioka, H., & Zhu, X. (2008). Dynamin-like protein 1 reduction underlies mitochondrial morphology and distribution abnormalities in fibroblasts from sporadic Alzheimer`s disease patients. The American journal of pathology, 173(2), 470-482.Wang, X., Su, B., Siedlak, S. L., Moreira, P. I., Fujioka, H., Wang, Y., . . . Zhu, X. (2008). Amyloid-β overproduction causes abnormal mitochondrial dynamics via differential modulation of mitochondrial fission/fusion proteins. Proc Natl Acad Sci U S A, 105(49), 19318-19323. doi:10.1073/pnas.0804871105Wang, X., Su, B., Siedlak, S. L., Moreira, P. I., Fujioka, H., Wang, Y., . . . Zhu, X. (2008). Amyloid-β overproduction causes abnormal mitochondrial dynamics via differential modulation of mitochondrial fission/fusion proteins. Proceedings of the National Academy of Sciences, 105(49), 19318-19323.Wilkins, H. M., Carl, S. M., Greenlief, A., Festoff, B. W., & Swerdlow, R. H. (2014). Bioenergetic dysfunction and inflammation in Alzheimer’s disease: a possible connection. Frontiers in aging neuroscience, 6, 311.Wu, S. N., Chern, J. H., Shen, S., Chen, H. H., Hsu, Y. T., Lee, C. C., . . . Shie, F. S. (2017). Stimulatory actions of a novel thiourea derivative on large‐conductance, calcium‐activated potassium channels. Journal of cellular physiology, 232(12), 3409-3421.Yao, J., Irwin, R. W., Zhao, L., Nilsen, J., Hamilton, R. T., & Brinton, R. D. (2009). Mitochondrial bioenergetic deficit precedes Alzheimer`s pathology in female mouse model of Alzheimer`s disease. Proceedings of the National Academy of Sciences, 106(34), 14670-14675.Zhan, Y., Paolicelli, R. C., Sforazzini, F., Weinhard, L., Bolasco, G., Pagani, F., . . . Ragozzino, D. (2014). Deficient neuron-microglia signaling results in impaired functional brain connectivity and social behavior. Nature neuroscience, 17(3), 400. 描述 碩士
國立政治大學
神經科學研究所
105754007資料來源 http://thesis.lib.nccu.edu.tw/record/#G0105754007 資料類型 thesis dc.contributor.advisor 詹銘煥 zh_TW dc.contributor.author (Authors) 孫儀馨 zh_TW dc.contributor.author (Authors) Sun, Yi-Sin en_US dc.creator (作者) 孫儀馨 zh_TW dc.creator (作者) Sun, Yi-Sin en_US dc.date (日期) 2018 en_US dc.date.accessioned 1-Oct-2018 12:12:04 (UTC+8) - dc.date.available 1-Oct-2018 12:12:04 (UTC+8) - dc.date.issued (上傳時間) 1-Oct-2018 12:12:04 (UTC+8) - dc.identifier (Other Identifiers) G0105754007 en_US dc.identifier.uri (URI) http://nccur.lib.nccu.edu.tw/handle/140.119/120265 - dc.description (描述) 碩士 zh_TW dc.description (描述) 國立政治大學 zh_TW dc.description (描述) 神經科學研究所 zh_TW dc.description (描述) 105754007 zh_TW dc.description.abstract (摘要) 阿茲海默氏症 (Alzheimer’s disease) 是一種常見的神經退化性疾病，其特徵為大腦中神經細胞漸進性的損傷以及微膠質細胞的過度活化。除此之外，β-澱粉樣蛋白 (Aβ) 的堆積是阿茲海默氏症中重要的病理特徵，並在疾病的發展中扮演重要的角色。由於β-澱粉樣蛋白的製造與清除失衡，使得β-澱粉樣蛋白產生堆積。而過多的β-澱粉樣蛋白會過度活化微膠質細胞，也會引發神經細胞之粒線體功能缺陷。病理過程造成慢性神經性發言及神經性退化的後果，最終導致神經元死亡。然而，β-澱粉樣蛋白對於微膠質細胞之粒線體的影響以及相關機制，卻較少被探討。因此，我們假設β-澱粉樣蛋白會引起微膠質細胞中粒線體功能的損傷，並間接影響微膠質細胞所調控的免疫發炎反應。本研究將微膠質細胞暴露在β-澱粉樣蛋白下，並檢測其粒線體的功能，包含生物能量（bioenergetics）、粒線體形態，以及相關訊號傳遞路徑的變化。此外，一個新型硫脲小分子藥物＃326，由於具有抗發炎能力，因此本篇研究進一步測試＃326是否能透過抗發炎的反應，來挽救受到β-澱粉樣蛋白所導致的粒線體功能缺失。本篇研究結果顯示，β-澱粉樣蛋白會降低粒線體的生物能量及改變粒線體形態與分佈，造成微膠質細胞中粒線體的功能損害。此外，β-澱粉樣蛋白會促進微膠質細胞中ERK的磷酸化。然而，在β-澱粉樣蛋白的作用下，#326不僅能挽救粒線體的功能缺失，並能降低β-澱粉樣蛋白引發之ERK過度磷酸化。據此推斷，#326可能透過調解ERK的訊號傳遞路徑，改善β-澱粉樣蛋白引起的線粒體失能。總結以上，我們的研究結果顯示#326能改善β-澱粉樣蛋白對微膠質細胞中線粒體功能的損害，而這種粒線體保護功能，可能與其調解ERK1/2的過度磷酸化作用有關。此外，透過研究新型的硫脲小分子藥物#326的作用機制，或許能得到阿茲海默氏症病理研究的相關線索，甚至對神經退化性疾病的藥物治療發展中有所幫助。 zh_TW dc.description.abstract (摘要) Alzheimer’s disease (AD), a neurodegenerative disease, is characterized by the progressive neuronal loss and overactive microglia. Besides, amyloid-β (Aβ) is a histopathological hallmark in AD, which plays a crucial role in the pathogenesis of this disease. The imbalance between Aβ production and clearance leads to the accumulation of Aβ in extracellular and intracellular compartments. Growing evidence suggests that excessive amyloid-β (Aβ) accumulation instigates early deficits in mitochondrial function and causes a self-propelling degeneration cycle which sustains chronic neuroinflammation induced by microglial and eventually lead to neuronal damages. Nevertheless, how Aβ affects mitochondrial function in microglia is still elusive. In this study, it was hypothesized that Aβ would cause mitochondrial defects in microglia and further exacerbate microglial activation which is the causation of neuronal inflammation in AD.To investigate this premise, mitochondrial function, including mitochondrial bioenergetics, mitochondrial morphology, and mitochondrial relative pathway were tested in microglial cells challenged with Aβ. In addition, the protective effects of a novel thiourea, compound #326, which possesses anti-inflammatory effect were also been examined in this study. Our data indicated that Aβ impaired mitochondrial function as evidenced by the decreased bioenergetics, fragmented mitochondria, and abnormal distribution. In addition, our results also showed the activation of extracellular-signal regulated kinase (ERK) phosphorylation under Aβ stimulation. Intriguingly, our data indicated that the rescuing effects of the novel compound on the aberrant bioenergetics elicited by Aβ are involved in the modulation of ERK activity that is highly associated with mitochondrial damages under the circumstances of Aβ toxicity. Therefore, studying the mechanism of the new thiourea, compound #326, may provide the clues to study the pathology of AD, and even improve the design of pharmacological intervention for AD. en_US dc.description.tableofcontents Approval page IAcknowledgements IIAbstract IIIThe list of Tables IXThe list of Figures IXThe list of Abbreviations XChapter 1. Introduction XI1.1 Alzheimer’s disease 11.2 Amyloid β 21.3 Mitochondrial dysfunction caused by Aβ 31.4 Mitochondrial defects in AD 41.5 Mitochondrial defects in microglia during the pathogenesis of AD. 51.6 Mitochondrial bioenergetics in AD 81.7 Morphological changes in mitochondria 91.8 Inflammation and mitochondrial dysfunction 91.9 BKCa channel 101.10 Hypothesis 111.11 The approaches and the findings 11Chapter 2. Materials and Methods 132.1 Cell culture 132.1.1 SM826 microglial cell culture 132.1.2 Primary microglial cell culture 132.2 Aβ oligomerization and treatment 142.3 Compound #326 preparation 142.4 Real time quantitative reverse transcription PCR 152.5 Western blot assay 152.5.1 Total protein extraction 162.5.2 Protein measurement - PierceTM BCA Protein Assay 162.5.3 Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) 162.5.4 Western blot imaging 172.6 Live cell staining for mitochondrial morphology 182.7 Immunoflourescence microscopy and high resolution confocal imaging 182.8 Skeletonized images of mitochondria 192.9 Mitochondrial bioenergetic measurements 192.10 Statistical analysis 20Chapter 3. Results 213.1 Aβ-induced mitochondrial bioenergetic dysfunction in microglial cells 213.2 Aβ-induced mitochondrial morphological changes in primary microglial cells 223.3 The effect of Aβ on the expression of genes related to mitochondrial morphology 233.4 The possible connection between mitochondrial morphology and inflammation 24Chapter 4. Discussion 26Tables 31Figures 32Reference 46 zh_TW dc.format.extent 6125109 bytes - dc.format.mimetype application/pdf - dc.source.uri (資料來源) http://thesis.lib.nccu.edu.tw/record/#G0105754007 en_US dc.subject (關鍵詞) 阿茲海默氏症 zh_TW dc.subject (關鍵詞) 微膠質細胞 zh_TW dc.subject (關鍵詞) β-澱粉樣蛋白 zh_TW dc.subject (關鍵詞) 粒線體 zh_TW dc.subject (關鍵詞) 生物能量 zh_TW dc.subject (關鍵詞) 硫脲 zh_TW dc.subject (關鍵詞) Alzheimer’s disease en_US dc.subject (關鍵詞) Microglia en_US dc.subject (關鍵詞) Beta-amyloid en_US dc.subject (關鍵詞) Mitochondria en_US dc.subject (關鍵詞) Bioenergetics en_US dc.subject (關鍵詞) Thiourea en_US dc.title (題名) 新型抗發炎硫脲小分子藥物能改善微膠質細胞因β-澱粉樣蛋白所引起之粒線體功能缺失 zh_TW dc.title (題名) A novel thiourea possessing anti-inflammatory property rescues Aβ-induced mitochondrial dysfunction in microglia en_US dc.type (資料類型) thesis en_US dc.relation.reference (參考文獻) Association, A. s. (2018). 2018 Alzheimer`s disease facts and figures. Alzheimer`s & Dementia, 14(3), 367-429.Ballweg, K., Mutze, K., Königshoff, M., Eickelberg, O., & Meiners, S. (2014). Cigarette smoke extract affects mitochondrial function in alveolar epithelial cells. American Journal of Physiology-Lung Cellular and Molecular Physiology, 307(11), L895-L907.Baloyannis, S. J. (2006). Mitochondrial alterations in Alzheimer`s disease. Journal of Alzheimer`s Disease, 9(2), 119-126.Bernhart, E., Kollroser, M., Rechberger, G., Reicher, H., Heinemann, A., Schratl, P., . . . DeVaney, T. (2010). Lysophosphatidic acid receptor activation affects the C13NJ microglia cell line proteome leading to alterations in glycolysis, motility, and cytoskeletal architecture. Proteomics, 10(1), 141-158.Berridge, M. J. (2013). Dysregulation of neural calcium signaling in Alzheimer disease, bipolar disorder and schizophrenia. Prion, 7(1), 2-13.Blass, J. P., Sheu, R. K., & Gibson, G. E. (2000). Inherent abnormalities in energy metabolism in Alzheimer disease. Interaction with cerebrovascular compromise. Ann N Y Acad Sci, 903, 204-221.Brand, M. D., & Nicholls, D. G. (2011). Assessing mitochondrial dysfunction in cells. Biochemical Journal, 435(2), 297-312.Cabezas-Opazo, F. A., Vergara-Pulgar, K., Pérez, M. J., Jara, C., Osorio-Fuentealba, C., & Quintanilla, R. A. (2015). Mitochondrial dysfunction contributes to the pathogenesis of Alzheimer’s disease. Oxidative medicine and cellular longevity, 2015.Cabezas-Opazo, F. A., Vergara-Pulgar, K., Perez, M. J., Jara, C., Osorio-Fuentealba, C., & Quintanilla, R. A. (2015). Mitochondrial Dysfunction Contributes to the Pathogenesis of Alzheimer`s Disease. Oxid Med Cell Longev, 2015, 509654. doi:10.1155/2015/509654Cai, Z., Hussain, M. D., & Yan, L.-J. (2014). Microglia, neuroinflammation, and beta-amyloid protein in Alzheimer`s disease. International Journal of Neuroscience, 124(5), 307-321.Chacko, B. K., Kramer, P. A., Ravi, S., Benavides, G. A., Mitchell, T., Dranka, B. P., . . . Bailey, S. M. (2014). The Bioenergetic Health Index: a new concept in mitochondrial translational research. Clinical science, 127(6), 367-373.Chénais, B., Morjani, H., & Drapier, J. C. (2002). Impact of endogenous nitric oxide on microglial cell energy metabolism and labile iron pool. Journal of neurochemistry, 81(3), 615-623.Chern, J.-H., Hsu, P.-C., Wang, L.-W., Tsay, H.-J., Kang, I.-J., & Shie, F.-S. (2010). Modulation of microglial immune responses by a novel thiourea derivative. Chemico-biological interactions, 188(1), 228-236.Chow, V. W., Mattson, M. P., Wong, P. C., & Gleichmann, M. (2010). An overview of APP processing enzymes and products. Neuromolecular medicine, 12(1), 1-12.Condello, C., Yuan, P., & Grutzendler, J. (2017). Microglia-mediated neuroprotection, TREM2 and Alzheimer’s disease: Evidence from Optical Imaging. Biological psychiatry.Cuello, A. C. (2005). Intracellular and extracellular Aβ, a tale of two neuropathologies. Brain Pathology, 15(1), 66-71.Cummings, J. L., Morstorf, T., & Zhong, K. (2014). Alzheimer’s disease drug-development pipeline: few candidates, frequent failures. Alzheimer`s Research & Therapy, 6(4), 37. doi:10.1186/alzrt269De Felice, F. G., & Ferreira, S. T. (2014). Inflammation, defective insulin signaling, and mitochondrial dysfunction as common molecular denominators connecting type 2 diabetes to Alzheimer disease. Diabetes, DB_131954.Dranka, B. P., Hill, B. G., & Darley-Usmar, V. M. (2010). Mitochondrial reserve capacity in endothelial cells: The impact of nitric oxide and reactive oxygen species. Free Radic Biol Med, 48(7), 905-914. doi:10.1016/j.freeradbiomed.2010.01.015Du, H., Guo, L., Yan, S., Sosunov, A. A., McKhann, G. M., & Yan, S. S. (2010). Early deficits in synaptic mitochondria in an Alzheimer`s disease mouse model. Proceedings of the National Academy of Sciences, 201006586.Fu, W., Vukojevic, V., Patel, A., Soudy, R., MacTavish, D., Westaway, D., . . . Jhamandas, J. (2017). Role of microglial amylin receptors in mediating beta amyloid (Aβ)-induced inflammation. Journal of neuroinflammation, 14(1), 199.Galloway, C. A., Lee, H., & Yoon, Y. (2012). Mitochondrial morphology—emerging role in bioenergetics. Free Radical Biology and Medicine, 53(12), 2218-2228.Gupta, K. J., Igamberdiev, A. U., & Mur, L. A. (2012). NO and ROS homeostasis in mitochondria: a central role for alternative oxidase. New Phytologist, 195(1), 1-3.Hay, S. I., Abajobir, A. A., Abate, K. H., Abbafati, C., Abbas, K. M., Abd-Allah, F., . . . Abera, S. F. (2017). Global, regional, and national disability-adjusted life-years (DALYs) for 333 diseases and injuries and healthy life expectancy (HALE) for 195 countries and territories, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. The Lancet, 390(10100), 1260-1344.Hayashi, Y., Morinaga, S., Zhang, J., Satoh, Y., Meredith, A. L., Nakata, T., ... & Nakanishi, H. (2016). BK channels in microglia are required for morphine-induced hyperalgesia. Nature communications, 7, 11697.Hirai, K., Aliev, G., Nunomura, A., Fujioka, H., Russell, R. L., Atwood, C. S., . . . Tabaton, M. (2001). Mitochondrial abnormalities in Alzheimer`s disease. Journal of Neuroscience, 21(9), 3017-3023.Huang, Z., Zhou, T., Sun, X., Zheng, Y., Cheng, B., Li, M., . . . He, C. (2017). Necroptosis in microglia contributes to neuroinflammation and retinal degeneration through TLR4 activation. Cell Death And Differentiation, 25, 180. doi:10.1038/cdd.2017.141https://www.nature.com/articles/cdd2017141#supplementary-informationHuang, Z., Zhou, T., Sun, X., Zheng, Y., Cheng, B., Li, M., . . . He, C. (2018). Necroptosis in microglia contributes to neuroinflammation and retinal degeneration through TLR4 activation. Cell death and differentiation, 25(1), 180.Itoh, K., Nakamura, K., Iijima, M., & Sesaki, H. (2013). Mitochondrial dynamics in neurodegeneration. Trends Cell Biol, 23(2), 64-71. doi:10.1016/j.tcb.2012.10.006Ježek, P., & Hlavatá, L. (2005). Mitochondria in homeostasis of reactive oxygen species in cell, tissues, and organism. The international journal of biochemistry & cell biology, 37(12), 2478-2503.Kashatus, J. A., Nascimento, A., Myers, L. J., Sher, A., Byrne, F. L., Hoehn, K. L., . . . Kashatus, D. F. (2015). Erk2 phosphorylation of Drp1 promotes mitochondrial fission and MAPK-driven tumor growth. Molecular cell, 57(3), 537-551.Kim, B., Park, J., Chang, K.-T., & Lee, D.-S. (2016). Peroxiredoxin 5 prevents amyloid-beta oligomer-induced neuronal cell death by inhibiting ERK–Drp1-mediated mitochondrial fragmentation. Free Radical Biology and Medicine, 90, 184-194.Kim, D. I., Lee, K. H., Oh, J. Y., Kim, J. S., & Han, H. J. (2017). Relationship Between beta-Amyloid and Mitochondrial Dynamics. Cell Mol Neurobiol, 37(6), 955-968. doi:10.1007/s10571-016-0434-4Kitamura, Y., Shimohama, S., Ota, T., Matsuoka, Y., Nomura, Y., & Taniguchi, T. (1997). Alteration of transcription factors NF-κB and STAT1 in Alzheimer`s disease brains. Neuroscience letters, 237(1), 17-20.Kogot-Levin, A., Saada, A., Leibowitz, G., Soiferman, D., Douiev, L., Raz, I., & Weksler-Zangen, S. (2016). Upregulation of Mitochondrial Content in Cytochrome c Oxidase Deficient Fibroblasts. PLoS ONE, 11(10), e0165417. doi:10.1371/journal.pone.0165417Kreutzberg, G. W. (1996). Microglia: a sensor for pathological events in the CNS. Trends in neurosciences, 19(8), 312-318.Langley, M., Ghosh, A., Charli, A., Sarkar, S., Ay, M., Luo, J., . . . Jin, H. (2017). Mito-apocynin prevents mitochondrial dysfunction, microglial activation, oxidative damage, and progressive neurodegeneration in mitopark transgenic mice. Antioxidants & redox signaling, 27(14), 1048-1066.Li, C., Yang, F., Liu, F., Li, D., & Yang, T. (2018). NRF2/HO-1 activation via ERK pathway involved in the anti-neuroinflammatory effect of Astragaloside IV in LPS induced microglial cells. Neuroscience letters, 666, 104-110.Li, M., Chen, L., Lee, D. H. S., Yu, L.-C., & Zhang, Y. (2007). The role of intracellular amyloid β in Alzheimer`s disease. Progress in neurobiology, 83(3), 131-139.Logsdon, R. G., Gibbons, L. E., McCurry, S. M., & Teri, L. (1999). Quality of life in Alzheimer`s disease: patient and caregiver reports. Journal of Mental health and Aging, 5, 21-32.Lu, R., Lukowski, R., Sausbier, M., Zhang, D. D., Sisignano, M., Schuh, C. D., ... &. Schmidtko, A. (2014). BK Ca channels expressed in sensory neurons modulate inflammatory pain in mice. PAIN®, 155(3), 556-565.Lyck, L., Santamaria, I. D., Pakkenberg, B., Chemnitz, J., Schrøder, H. D., Finsen, B., & Gundersen, H. J. G. (2009). An empirical analysis of the precision of estimating the numbers of neurons and glia in human neocortex using a fractionator-design with sub-sampling. Journal of neuroscience methods, 182(2), 143-156.Manczak, M., Calkins, M. J., & Reddy, P. H. (2011). Impaired mitochondrial dynamics and abnormal interaction of amyloid beta with mitochondrial protein Drp1 in neurons from patients with Alzheimer`s disease: implications for neuronal damage. Human molecular genetics, 20(13), 2495-2509.Miklossy, J., Kis, A., Radenovic, A., Miller, L., Forro, L., Martins, R., . . . Mihaly, L. (2006). Beta-amyloid deposition and Alzheimer`s type changes induced by Borrelia spirochetes. Neurobiology of aging, 27(2), 228-236.Morales, I., Guzmán-Martínez, L., Cerda-Troncoso, C., Farías, G. A., & Maccioni, R. B. (2014). Neuroinflammation in the pathogenesis of Alzheimer’s disease. A rational framework for the search of novel therapeutic approaches. Frontiers in cellular neuroscience, 8, 112.Moreira, P., Cardoso, S., Santos, M., & Oliveira, C. (2006). The key role of mitochondria in Alzheimer`s disease. Journal of Alzheimer`s Disease, 9(2), 101-110.Moreira, P. I., Carvalho, C., Zhu, X., Smith, M. A., & Perry, G. (2010). Mitochondrial dysfunction is a trigger of Alzheimer`s disease pathophysiology. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 1802(1), 2-10. doi:https://doi.org/10.1016/j.bbadis.2009.10.006Morkuniene, R., Cizas, P., Jankeviciute, S., Petrolis, R., Arandarcikaite, O., Krisciukaitis, A., & Borutaite, V. (2015). Small Aβ1–42 oligomer‐induced membrane depolarization of neuronal and microglial cells: Role of N‐methyl‐D‐aspartate receptors. Journal of neuroscience research, 93(3), 475-486.Morris, G. P., Clark, I. A., Zinn, R., & Vissel, B. (2013). Microglia: a new frontier for synaptic plasticity, learning and memory, and neurodegenerative disease research. Neurobiology of learning and memory, 105, 40-53.Morris, J. C. (2012). Revised criteria for mild cognitive impairment may compromise the diagnosis of Alzheimer disease dementia. Archives of neurology, 69(6), 700-708.Moss, D. W., & Bates, T. E. (2001). Activation of murine microglial cell lines by lipopolysaccharide and interferon‐γ causes NO‐mediated decreases in mitochondrial and cellular function. European Journal of Neuroscience, 13(3), 529-538.Nakajima, K., & Kohsaka, S. (2004). Microglia: neuroprotective and neurotrophic cells in the central nervous system. Curr Drug Targets Cardiovasc Haematol Disord, 4(1), 65-84.Onyango, I. G. (2018). Modulation of mitochondrial bioenergetics as a therapeutic strategy in Alzheimer`s disease. Neural Regen Res, 13(1), 19-25. doi:10.4103/1673-5374.224362Onyango, I. G., Dennis, J., & Khan, S. M. (2016). Mitochondrial dysfunction in Alzheimer’s disease and the rationale for bioenergetics based therapies. Aging and disease, 7(2), 201.Orihuela, R., McPherson, C. A., & Harry, G. J. (2016). Microglial M1/M2 polarization and metabolic states. British journal of pharmacology, 173(4), 649-665.Palacino, J. J., Sagi, D., Goldberg, M. S., Krauss, S., Motz, C., Wacker, M., . . . Shen, J. (2004). Mitochondrial dysfunction and oxidative damage in parkin-deficient mice. J Biol Chem, 279(18), 18614-18622. doi:10.1074/jbc.M401135200Park, J., Min, J.-S., Kim, B., Chae, U.-B., Yun, J. W., Choi, M.-S., . . . Lee, D.-S. (2015). Mitochondrial ROS govern the LPS-induced pro-inflammatory response in microglia cells by regulating MAPK and NF-κB pathways. Neuroscience letters, 584, 191-196.Park, L. C., Zhang, H., Sheu, K. F. R., Calingasan, N. Y., Kristal, B. S., Gordon Lindsay, J., & Gibson, G. E. (1999). Metabolic impairment induces oxidative stress, compromises inflammatory responses, and inactivates a key mitochondrial enzyme in microglia. Journal of neurochemistry, 72(5), 1948-1958.Pérez, M. J., Jara, C., Muñoz‐Urrutia, E., & Quintanilla, R. A. (2016). New Targets for Diagnosis and Treatment Against Alzheimer’s Disease: The Mitochondrial Approach Update on Dementia: InTech.Perry, C. G., Kane, D. A., Lanza, I. R., & Neufer, P. D. (2013). Methods for assessing mitochondrial function in diabetes. Diabetes, 62(4), 1041-1053. doi:10.2337/db12-1219Picard, M., Shirihai, O. S., Gentil, B. J., & Burelle, Y. (2013). Mitochondrial morphology. transitions and functions: implications for retrograde signaling?. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 304(6), R393-R406.Pinho, C. M., Teixeira, P. F., & Glaser, E. (2014). Mitochondrial import and degradation of amyloid-β peptide. Biochimica et Biophysica Acta (BBA)-Bioenergetics, 1837(7), 1069-1074.Pouysségur, J., & Lenormand, P. (2016). ERK1 and ERK2 map kinases: specific roles or functional redundancy? Frontiers in cell and developmental biology, 4, 53.Qi, X., Qvit, N., Su, Y. C., & Mochly-Rosen, D. (2013). A novel Drp1 inhibitor diminishes aberrant mitochondrial fission and neurotoxicity. J Cell Sci, 126(Pt 3), 789-802. doi:10.1242/jcs.114439Rambold, A. S., & Pearce, E. L. (2017). Mitochondrial dynamics at the interface of immune cell metabolism and function. Trends in immunology.Ransohoff, R. M. (2016). A polarizing question: do M1 and M2 microglia exist? Nature neuroscience, 19(8), 987.Reemst, K., Noctor, S. C., Lucassen, P. J., & Hol, E. M. (2016). The indispensable roles of microglia and astrocytes during brain development. Frontiers in human neuroscience, 10, 566.Sangiuliano, B., Pérez, N. M., Moreira, D. F., & Belizário, J. E. (2014). Cell death-associated. molecular-pattern molecules: inflammatory signaling and control. Mediators of inflammation, 2014.Sarkar, S., Malovic, E., Harishchandra, D. S., Ghaisas, S., Panicker, N., Charli, A., . . . Anantharam, V. (2017). Mitochondrial impairment in microglia amplifies NLRP3 inflammasome proinflammatory signaling in cell culture and animal models of Parkinson’s disease. NPJ Parkinson`s disease, 3(1), 30.Sarlus, H., & Heneka, M. T. (2017). Microglia in Alzheimer’s disease. The Journal of clinical investigation, 127(9), 3240-3249.Schilling, T., Stock, C., Schwab, A., & Eder, C. (2004). Functional importance of Ca2+‐activated K+ channels for lysophosphatidic acid‐induced microglial migration. European Journal of Neuroscience, 19(6), 1469-1474.Sengupta, U., Nilson, A. N., & Kayed, R. (2016). The role of amyloid-β oligomers in toxicity, propagation, and immunotherapy. EBioMedicine, 6, 42-49.Shie, F. S., Breyer, R. M., & Montine, T. J. (2005). Microglia Lacking E Prostanoid Receptor Subtype 2 Have Enhanced Aβ Phagocytosis yet Lack Aβ-Activated Neurotoxicity. Am J Pathol, 166(4), 1163-1172.Shirendeb, U., Reddy, A. P., Manczak, M., Calkins, M. J., Mao, P., Tagle, D. A., & Hemachandra Reddy, P. (2011). Abnormal mitochondrial dynamics, mitochondrial loss and mutant huntingtin oligomers in Huntington`s disease: implications for selective neuronal damage. Human molecular genetics, 20(7), 1438-1455.Smith, R. A., Hartley, R. C., Cocheme, H. M., & Murphy, M. P. (2012). Mitochondrial pharmacology. Trends in pharmacological sciences, 33(6), 341-352.Son, J. M., Sarsour, E. H., Kakkerla Balaraju, A., Fussell, J., Kalen, A. L., Wagner, B. A., . . . Goswami, P. C. (2017). Mitofusin 1 and optic atrophy 1 shift metabolism to mitochondrial respiration during aging. Aging cell, 16(5), 1136-1145.Spuch, C., Ortolano, S., & Navarro, C. (2012). New insights in the amyloid-Beta interaction with mitochondria. Journal of aging research, 2012.Standridge, J. B. (2006). Vicious cycles within the neuropathophysiologic mechanisms of Alzheimer`s disease. Current Alzheimer Research, 3(2), 95-107.Swerdlow, R. H. (2017). Mitochondria and mitochondrial cascades in Alzheimer’s disease. Journal of Alzheimer`s Disease(Preprint), 1-14.Tammineni, P., Jeong, Y. Y., Feng, T., Aikal, D., & Cai, Q. (2017). Impaired axonal retrograde trafficking of the retromer complex augments lysosomal deficits in Alzheimer’s disease neurons. Human molecular genetics, 26(22), 4352-4366.Tanhehco, E. J. (2001). Potassium channel modulators as anti-inflammatory agents. Expert Opinion on Therapeutic Patents, 11(7), 1137-1145. doi:10.1517/13543776.11.7.1137Trevisan, T., Pendin, D., Montagna, A., Bova, S., Ghelli, A. M., & Daga, A. (2018). Manipulation of Mitochondria Dynamics Reveals Separate Roles for Form and Function in Mitochondria Distribution. Cell reports, 23(6), 1742-1753.Trimmer, P. A., & Borland, M. K. (2005). Differentiated Alzheimer`s disease transmitochondrial cybrid cell lines exhibit reduced organelle movement. Antioxidants & redox signaling, 7(9-10), 1101-1109.Urrutia, P. J., Mena, N. P., & Nunez, M. T. (2014). The interplay between iron accumulation, mitochondrial dysfunction, and inflammation during the execution step of neurodegenerative disorders. Frontiers in pharmacology, 5, 38.Valente, A. J., Maddalena, L. A., Robb, E. L., Moradi, F., & Stuart, J. A. (2017). A simple ImageJ macro tool for analyzing mitochondrial network morphology in mammalian cell culture. Acta histochemica, 119(3), 315-326.Velliquette, R. A., O`Connor, T., & Vassar, R. (2005). Energy inhibition elevates β-secretase levels and activity and is potentially amyloidogenic in APP transgenic mice: possible early events in Alzheimer`s disease pathogenesis. Journal of Neuroscience, 25(47), 10874-10883.Von Bernhardi, R., Eugenín-von Bernhardi, L., & Eugenín, J. (2015). Microglial cell dysregulation in brain aging and neurodegeneration. Frontiers in aging neuroscience, 7, 124.Wang, W.-Y., Tan, M.-S., Yu, J.-T., & Tan, L. (2015). Role of pro-inflammatory cytokines released from microglia in Alzheimer’s disease. Annals of translational medicine, 3(10).Wang, X., Su, B., Fujioka, H., & Zhu, X. (2008). Dynamin-like protein 1 reduction underlies mitochondrial morphology and distribution abnormalities in fibroblasts from sporadic Alzheimer`s disease patients. The American journal of pathology, 173(2), 470-482.Wang, X., Su, B., Siedlak, S. L., Moreira, P. I., Fujioka, H., Wang, Y., . . . Zhu, X. (2008). Amyloid-β overproduction causes abnormal mitochondrial dynamics via differential modulation of mitochondrial fission/fusion proteins. Proc Natl Acad Sci U S A, 105(49), 19318-19323. doi:10.1073/pnas.0804871105Wang, X., Su, B., Siedlak, S. L., Moreira, P. I., Fujioka, H., Wang, Y., . . . Zhu, X. (2008). Amyloid-β overproduction causes abnormal mitochondrial dynamics via differential modulation of mitochondrial fission/fusion proteins. Proceedings of the National Academy of Sciences, 105(49), 19318-19323.Wilkins, H. M., Carl, S. M., Greenlief, A., Festoff, B. W., & Swerdlow, R. H. (2014). Bioenergetic dysfunction and inflammation in Alzheimer’s disease: a possible connection. Frontiers in aging neuroscience, 6, 311.Wu, S. N., Chern, J. H., Shen, S., Chen, H. H., Hsu, Y. T., Lee, C. C., . . . Shie, F. S. (2017). Stimulatory actions of a novel thiourea derivative on large‐conductance, calcium‐activated potassium channels. Journal of cellular physiology, 232(12), 3409-3421.Yao, J., Irwin, R. W., Zhao, L., Nilsen, J., Hamilton, R. T., & Brinton, R. D. (2009). Mitochondrial bioenergetic deficit precedes Alzheimer`s pathology in female mouse model of Alzheimer`s disease. Proceedings of the National Academy of Sciences, 106(34), 14670-14675.Zhan, Y., Paolicelli, R. C., Sforazzini, F., Weinhard, L., Bolasco, G., Pagani, F., . . . Ragozzino, D. (2014). Deficient neuron-microglia signaling results in impaired functional brain connectivity and social behavior. Nature neuroscience, 17(3), 400. zh_TW dc.identifier.doi (DOI) 10.6814/THE.NCCU.IN.006.2018.C05 en_US
