| 研究生: |
廖崇賢 Liao, Chung-Hsien |
|---|---|
| 論文名稱: |
血紅素與貝他糊蛋白的交互作用 The interaction of hemoglobin and β-amyloid peptide |
| 指導教授: |
吳豐森
Wu, Fong-Sen |
| 學位類別: |
碩士 Master |
| 系所名稱: |
醫學院 - 生理學研究所 Department of Physiology |
| 論文出版年: | 2011 |
| 畢業學年度: | 99 |
| 語文別: | 英文 |
| 論文頁數: | 30 |
| 中文關鍵詞: | 貝他糊蛋白結合蛋白 、血紅素 、阿茲海默氏症 |
| 外文關鍵詞: | amyloid-β binding protein, hemoglobin, Alzheimer’s disease |
| 相關次數: | 點閱:82 下載:5 |
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阿茲海默症(Alzheimer's disease)是一種漸進式的神經退化性疾病。主要的病理特徵有貝他糊蛋白斑塊沈澱於細胞外及神經纖維糾結聚集於神經細胞內。貝他糊蛋白斑塊最主要的成份是貝他糊蛋白;係由細胞膜上的前趨蛋白經由酵素切割而成。在腦中,貝他糊蛋白可能與其他蛋白結合,導致其加速聚集或減弱被代謝的可能。血紅素(Hemoglobin)是一種被研究許久的球蛋白,其在人體最重要的功能是在紅血球中攜帶氧氣。先前的研究發現,血紅素出現在類澱粉蛋白斑塊的沈積中,也發現血紅素可與貝他糊蛋白結合。然而儘管血紅素可以在阿茲海默氏症患者的血漿與腦組織和貝他糊蛋白一起分離出來,這些血紅素是來自血管中的紅血球,或者是腦中的細胞卻無法確認。有研究指出腦中細胞可以表現血紅素,然而由何種細胞所表現卻仍不清楚。本研究的目的是探討血紅素對貝他糊蛋白聚集的影響,並找出哪些腦內細胞會生成血紅素。首先,以試管中加入血紅素與貝他糊蛋白培養發現,血紅素不但能夠依量促進貝他糊蛋白的聚集,也會隨培養時間增加,依時促進貝他糊蛋白的聚集。然而,在電子顯微鏡底下,貝他糊蛋白的纖維化並不受血紅素影響。在人類腦組織切片中,血紅素會出現在顳葉的寡突細胞細胞本體和神經元細胞質中。其中尤其是寡突細胞—幾乎所有的寡突細胞細胞本體都有血紅素的存在。此外,極少數的星狀細胞與微膠細胞(<5%)也表現有血紅素。總結本研究顯示,血紅素只在貝他糊蛋白聚集的初期有促進作用;大腦中主要表現血紅素的細胞是寡突細胞和神經元。
Alzheimer’s disease (AD) is an age-related neurodegenerative disorder characterized pathologically by the presence of extracellular senile plaques and intraneuronal neurofibrillary tangles. The main component of senile plaques is the β-amyloid (Aβ) peptides derived from the larger precursor protein, AβPP. It has been postulated that binding of some molecules to Aβ are responsible for the promotion of accumulation or increase of stability of amyloid in AD. Hemoglobin (Hb), is the oxygen- and carbon dioxide-carrying protein responsible for oxygen delivery to the tissues. Previously, Hb was identified as a potent Aβ binding protein and found to be co-localized with Aβ in amyloid plaques and cerebral amyloid angiopathy. Though Hb has been co-immunoprecipitated with Aβ from both AD brains and plasma, whether Hb is derived from circulation or from brain cells remain elusive. The objective of this study is to characterize the possible role of Hb on Aβ aggregation and the expression of Hb in the brain. In vitro studies showed that the Hb promoted Aβ aggregation in a time and dose dependent manner. However, under the electron microscopy, Hb did not alter the fibrilization of Aβ Hb immunoreactivity was found in a subpopulation of hippocampal and cortical neurons in human postmortem temporal lobe. Among them, Hb expressed in the cell bodies of almost all the oligodendrocytes. Hb immunoreactivity was also evident in neuronal cell, although to a lesser degree. Occasionally, Hb immunoreactivity could be found in a very limited number of astrocytes and microglia. Taken together, these studies suggest that Hb promotes the initial phase of Aβ oligomerization, but not the later polymerization phase. Hb is primarily expressed in the oligodendrocyte and neuron.
Atamna, H., and Boyle, K. (2006). Amyloid-β peptide binds with heme to form a peroxidase: Relationship to the cytopathologies of Alzheimer’s disease. Proceedings of the National Academy of Sciences of the United States of America 103, 3381 -3386.
Biagioli, M., Pinto, M., Cesselli, D., Zaninello, M., Lazarevic, D., Roncaglia, P., Simone, R., Vlachouli, C., Plessy, C., Bertin, N., et al. (2009). Unexpected expression of alpha- and beta-globin in mesencephalic dopaminergic neurons and glial cells. Proc. Natl. Acad. Sci. U.S.A 106, 15454-15459.
Blalock, E. M., Chen, K., Sharrow, K., Herman, J. P., Porter, N. M., Foster, T. C., and Landfield, P. W. (2003). Gene microarrays in hippocampal aging: statistical profiling identifies novel processes correlated with cognitive impairment. J. Neurosci 23, 3807-3819.
Bush, A. I. (2003). The metallobiology of Alzheimer's disease. Trends in Neurosciences 26, 207-214.
Chiueh, C. C. (2001). Iron overload, oxidative stress, and axonal dystrophy in brain disorders1. Pediatric neurology 25, 138–147.
Dassen, H., Kamps, R., Punyadeera, C., Dijcks, F., de Goeij, A., Ederveen, A., Dunselman, G., and Groothuis, P. (2008). Haemoglobin expression in human endometrium. Hum. Reprod 23, 635-641.
Gandy, S. (2005). The role of cerebral amyloid beta accumulation in common forms of Alzheimer disease. J. Clin. Invest 115, 1121-1129.
Götz, M. E., Freyberger, A., and Riederer, P. (1990). Oxidative stress: a role in the pathogenesis of Parkinson's disease. J. Neural Transm. Suppl 29, 241-249.
Hardy, J., and Selkoe, D. J. (2002). The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 297, 353-356.
He, Y., Hua, Y., Liu, W., Hu, H., Keep, R. F., and Xi, G. (2008). Effects of cerebral ischemia on neuronal hemoglobin. Journal of Cerebral Blood Flow & Metabolism 29, 596–605.
Khan, A. A., Wang, Y., Sun, Y., Mao, X. O., Xie, L., Miles, E., Graboski, J., Chen, S., Ellerby, L. M., Jin, K., et al. (2006). Neuroglobin-overexpressing transgenic mice are resistant to cerebral and myocardial ischemia. Proc. Natl. Acad. Sci. U.S.A 103, 17944-17948.
Kuo, Y. M., Kokjohn, T. A., Kalback, W., Luehrs, D., Galasko, D. R., Chevallier, N., Koo, E. H., Emmerling, M. R., and Roher, A. E. (2000). Amyloid-beta peptides interact with plasma proteins and erythrocytes: implications for their quantitation in plasma. Biochem. Biophys. Res. Commun 268, 750-756.
Kuo, Y., Emmerling, M. R., Lampert, H. C., Hempelman, S. R., Kokjohn, T. A., Woods, A. S., Cotter, R. J., and Roher, A. E. (1999). High Levels of Circulating A[beta]42 Are Sequestered by Plasma Proteins in Alzheimer's Disease. Biochemical and Biophysical Research Communications 257, 787-791.
Liu, L., Zeng, M., and Stamler, J. S. (1999). Hemoglobin induction in mouse macrophages. Proc. Natl. Acad. Sci. U.S.A 96, 6643-6647.
Maurer, M. H., Frietsch, T., Waschke, K. F., Kuschinsky, W., Gassmann, M., and Schneider, A. (2002). Cerebral transcriptome analysis of transgenic mice overexpressing erythropoietin. Neurosci. Lett 327, 181-184.
Morris, J. C. (1997). Clinical assessment of Alzheimer's disease. Neurology 49, S7-10.
Newton, D. A., Rao, K. M. K., Dluhy, R. A., and Baatz, J. E. (2006). Hemoglobin is expressed by alveolar epithelial cells. J. Biol. Chem 281, 5668-5676.
Oyama, R., Yamamoto, H., and Titani, K. (2000). Glutamine synthetase, hemoglobin alpha-chain, and macrophage migration inhibitory factor binding to amyloid beta-protein: their identification in rat brain by a novel affinity chromatography and in Alzheimer's disease brain by immunoprecipitation. Biochim. Biophys. Acta 1479, 91-102.
Price, D. L., Tanzi, R. E., Borchelt, D. R., and Sisodia, S. S. (1998). ALZHEIMER'S DISEASE: Genetic Studies and Transgenic Models. Annu. Rev. Genet. 32, 461-493.
Richter, F., Meurers, B. H., Zhu, C., Medvedeva, V. P., and Chesselet, M. (2009). Neurons express hemoglobin alpha- and beta-chains in rat and human brains. J. Comp. Neurol 515, 538-547.
Schelshorn, D. W., Schneider, A., Kuschinsky, W., Weber, D., Krüger, C., Dittgen, T., Bürgers, H. F., Sabouri, F., Gassler, N., Bach, A., et al. (2008). Expression of hemoglobin in rodent neurons. Journal of Cerebral Blood Flow & Metabolism 29, 585–595.
Selkoe, D. J. (2001). Clearing the Brain's Amyloid Cobwebs. Neuron 32, 177-180.
Slemmon, J. R., Hughes, C. M., Campbell, G. A., and Flood, D. G. (1994). Increased levels of hemoglobin-derived and other peptides in Alzheimer's disease cerebellum. Journal of Neuroscience 14, 2225.
Sun, Y., Jin, K., Mao, X. O., Zhu, Y., and Greenberg, D. A. (2001). Neuroglobin is up-regulated by and protects neurons from hypoxic-ischemic injury. Proc. Natl. Acad. Sci. U.S.A 98, 15306-15311.
Sun, Y., Jin, K., Peel, A., Mao, X. O., Xie, L., and Greenberg, D. A. (2003). Neuroglobin protects the brain from experimental stroke in vivo. Proc. Natl. Acad. Sci. U.S.A 100, 3497-3500.
Vinogradov, S. N., and Moens, L. (2008). Diversity of Globin Function: Enzymatic, Transport, Storage, and Sensing. Journal of Biological Chemistry 283, 8773-8777.
Wang, G. L., and Semenza, G. L. (1993). General involvement of hypoxia-inducible factor 1 in transcriptional response to hypoxia. Proc. Natl. Acad. Sci. U.S.A 90, 4304-4308.
Wang, X., Mori, T., Sumii, T., and Lo, E. H. (2002). Hemoglobin-induced cytotoxicity in rat cerebral cortical neurons: caspase activation and oxidative stress. Stroke 33, 1882-1888.
Wride, M. A., Mansergh, F. C., Adams, S., Everitt, R., Minnema, S. E., Rancourt, D. E., and Evans, M. J. (2003). Expression profiling and gene discovery in the mouse lens. Mol. Vis 9, 360-396.
Wu, C., Liao, P., Yu, L., Wang, S., Chen, S., Wu, C., and Kuo, Y. (2004). Hemoglobin promotes Abeta oligomer formation and localizes in neurons and amyloid deposits. Neurobiol. Dis 17, 367-377.
Xi, G., Keep, R. F., and Hoff, J. T. (2006). Mechanisms of brain injury after intracerebral haemorrhage. Lancet Neurol 5, 53-63.
Zhao, X., Song, S., Sun, G., Strong, R., Zhang, J., Grotta, J. C., and Aronowski, J. (2009). Neuroprotective role of haptoglobin after intracerebral hemorrhage. J. Neurosci 29, 15819-15827.