Loading...
|
Please use this identifier to cite or link to this item:
https://nccur.lib.nccu.edu.tw/handle/140.119/112681
|
| Title: | 半乳糖凝集素-3促進乙型類澱粉蛋白寡聚合作用
Galectin-3 facilitates amyloid-beta oligomerization |
| Authors: | 鄭光閔
Zheng, Kuang Min |
| Contributors: | 李小媛
趙知章
Lee, Eminy H.Y.
Chao, Chih Chang
鄭光閔
Zheng, Kuang Min |
| Keywords: | 半乳糖凝集素-3
乙型類澱粉蛋白
寡聚合作用
腦啡肽酶
PIAS1
APP/PS1基因轉殖小鼠
Galectin-3
Aβ
Oligomerization
Neprilysin
PIAS1
APP/PS1 transgenic mice |
| Date: | 2017 |
| Issue Date: | 2017-09-13 14:49:49 (UTC+8) |
| Abstract: | 阿茲海默症是一種隨著年齡老化有關的神經退化性疾病，其特徵主要為記憶喪失及認知功能失調。阿茲海默症有兩個主要的病理指標，包含了因為濤蛋白造成的神經纖維糾結以及乙型類澱粉蛋白堆積而成的老化斑塊。乙型類澱粉蛋白是由類澱粉前驅蛋白經β-分泌酶及γ-分泌酶連續裁切生成大小約4-kDa的胜肽。乙型類澱粉蛋白會相互堆積形成寡聚體，並且高分子量寡聚體進一步再堆積成不可溶性的乙型類澱粉蛋白纖維及老化斑塊。半乳糖凝集素-3是半乳糖凝集素家族的一員，目前已知半乳糖凝集素-3調節各種細胞的功能，例如發炎、腫瘤生長以及細胞間的黏附，而在癌症中則有促使癌細胞積聚的能力，然而在大腦中的作用仍尚不清楚。在本研究中，我們使用APP/PS1基因轉殖小鼠作為阿茲海默症的動物模型，並且在其大腦中研究半乳糖凝集素-3對於乙型類澱粉蛋白堆積的作用與機制。結果顯示在野生型小鼠的海馬迴中過度表現半乳糖凝集素-3會促進乙型類澱粉蛋白的堆積，而將乙型類澱粉蛋白注射在半乳糖凝集素-3基因剔除小鼠的海馬迴，則會觀察到乙型類澱粉蛋白寡聚合作用的減少。乙型類澱粉蛋白的注射也會增加海馬迴中半乳糖凝集素-3的表現。在APP/PS1小鼠的海馬迴可以觀察到半乳糖凝集素-3的表現量會隨著年齡增長而增加，而具有抑制發炎及免疫反應的PIAS1在APP/PS1小鼠海馬迴中的表現量則會隨著年齡增長而減少。在探討半乳糖凝集素-3調節乙型類澱粉蛋白寡具體作用的過程中，我們發現半乳糖凝集素-3基因剔除小鼠的海馬迴中能夠代謝乙型類澱粉蛋白的腦啡肽酶表現量是野生型小鼠的兩倍多。研究結果顯示半乳糖凝集素-3對於乙型類澱粉蛋白的堆積扮演了重要的角色以及可能在阿茲海默症的病理機制中具有重要的作用。
Alzheimer’s disease (AD) is an age-related neurodegenerative disorder which is characterized by progressive loss of memory and other cognitive functions. The two pathological hallmarks of AD are extracellular amyloid plaque and flame-shaped neurofibrillary tangles of the tau protein. Aβ is a 4-kDa protein that is resulted from sequential cleavage of the amyloid precursor protein by beta-secretase and gamma-secretase. Once Aβ is produced, it will aggregate to form oligomers and high molecular weight (HMW) oligomers will further assemble to form large insoluble fibrils and plaque. Galectin-3 (Gal-3) is a member of the β-galactoside-binding galectin protein family. Gal-3 is known to regulate various cellular functions, such as inflammation, tumor progression and cell-cell adhesion. In cancer cell, Gal-3 enhances homotypic aggregation, but its role in the brain is much less known. In the present study, we examined the role and mechanism of Gal-3 in Aβ aggregation in the brain by adopting the APP/PS1 mice as an animal model of AD. Results revealed that overexpression of Gal-3 enhanced Aβ oligomerization, whereas Aβ injection into hippocampus of Gal-3 KO mice reduced Aβ oligomerization. Aβ injection also increased Gal-3 expression in the hippocampus. Gal-3 expression is also increased in APP/PS1 mice and this effect is more significant along with ageing. Meanwhile, the expression of protein inhibitor of activated STAT1 (PIAS1) that suppresses inflammation and immune response was decreased with ageing in APP/PS1 mice. We further found that the expression level of neprilysin, an enzyme that degrades Aβ, was increased for approximately two-folds in Gal-3 KO mice compared with WT mice. These results suggest that Gal-3 plays an important role in Aβ aggregation and possibly in the pathology of AD. |
| Reference: | Abdallah B, Hassan A, Benoist C, Goula D, Behr JP, Demeneix BA (1996) A powerful nonviral vector for in vivo gene transfer into the adult mammalian brain: polyethylenimine. Human gene therapy 7:1947-1954.
Almeida CG, Takahashi RH, Gouras GK (2006) Beta-amyloid accumulation impairs multivesicular body sorting by inhibiting the ubiquitin-proteasome system. The Journal of neuroscience : the official journal of the Society for Neuroscience 26:4277-4288.
Boletta A, Benigni A, Lutz J, Remuzzi G, Soria MR, Monaco L (1997) Nonviral gene delivery to the rat kidney with polyethylenimine. Human gene therapy 8:1243-1251.
Boza-Serrano A, Reyes JF, Rey NL, Leffler H, Bousset L, Nilsson U, Brundin P, Venero JL, Burguillos MA, Deierborg T (2014) The role of Galectin-3 in α-synuclein-induced microglial activation. Acta Neuropathologica Communications 2:156
Butterfield DA (2014) The 2013 discovery award from the society for free radical biology and medicine: selected discoveries from the butterfield laboratory of oxidative stress and its sequelae in brain in bognitive disorders exemplified by alzheimer disease and chemotherapy induced cognitive impairment. Free radical biology & medicine 0:157-174.
Cai Z, Hussain MD, Yan LJ (2014) Microglia, neuroinflammation, and beta-amyloid protein in Alzheimer`s disease. The International journal of neuroscience 124:307-321.
Calabresi PA (2004) Diagnosis and management of multiple sclerosis. American family physician 70:1935-1944.
Chen YC, Hsu WL, Ma YL, Tai DJ, Lee EH (2014) CREB SUMOylation by the E3 ligase PIAS1 enhances spatial memory. The Journal of neuroscience : the official journal of the Society for Neuroscience 34:9574-9589.
Chiou HY, Liu SY, Lin CH, Lee EH (2014) Hes-1 SUMOylation by protein inhibitor of activated STAT1 enhances the suppressing effect of Hes-1 on GADD45alpha expression to increase cell survival. Journal of biomedical science 21:53.
Cras P, Kawai M, Lowery D, Gonzalez-DeWhitt P, Greenberg B, Perry G (1991) Senile plaque neurites in Alzheimer disease accumulate amyloid precursor protein. Proceedings of the National Academy of Sciences of the United States of America 88:7552-7556.
Danilova N (2006) The evolution of immune mechanisms. Journal of experimental zoology Part B, Molecular and developmental evolution 306:496-520.
Diaz-Alvarez L, Ortega E (2017) The many roles of galectin-3, a multifaceted molecule, in innate immune responses against pathogens. Mediators of inflammation 2017:9247574.
Ehehalt R, Keller P, Haass C, Thiele C, Simons K (2003) Amyloidogenic processing of the Alzheimer beta-amyloid precursor protein depends on lipid rafts. The Journal of cell biology 160:113-123.
Esch FS, Keim PS, Beattie EC, Blacher RW, Culwell AR, Oltersdorf T, McClure D, Ward PJ (1990) Cleavage of amyloid beta peptide during constitutive processing of its precursor. Science 248:1122-1124.
Evin G, Weidemann A (2002) Biogenesis and metabolism of Alzheimer`s disease Abeta amyloid peptides. Peptides 23:1285-1297.
Fanselow MS, Dong HW (2010) Are the dorsal and ventral hippocampus functionally distinct structures? Neuron 65:7.
Fortuna-Costa A, Gomes AM, Kozlowski EO, Stelling MP, Pavao MS (2014) Extracellular galectin-3 in tumor progression and metastasis. Frontiers in oncology 4:138.
Frisch SM, Screaton RA (2001) Anoikis mechanisms. Current opinion in cell biology 13:555-562.
Golde TE, Koo EH, Felsenstein KM, Osborne BA, Miele L (2013) γ-Secretase Inhibitors and Modulators. Biochimica et biophysica acta 1828.
Gong CX, Shaikh S, Wang JZ, Zaidi T, Grundke-Iqbal I, Iqbal K (1995) Phosphatase activity toward abnormally phosphorylated tau: decrease in Alzheimer disease brain. Journal of neurochemistry 65:732-738.
Graeber MB, Kosel S, Grasbon-Frodl E, Moller HJ, Mehraein P (1998) Histopathology and APOE genotype of the first Alzheimer disease patient, Auguste D. Neurogenetics 1:223-228.
Haass C, Kaether C, Thinakaran G, Sisodia S (2012) Trafficking and Proteolytic Processing of APP. Cold Spring Harbor perspectives in medicine 2(5):a006270.
Hoyos HC, Rinaldi M, Mendez-Huergo SP, Marder M, Rabinovich GA, Pasquini JM, Pasquini LA (2014) Galectin-3 controls the response of microglial cells to limit cuprizone-induced demyelination. Neurobiology of disease 62:441-455.
Jeon SB, Yoon HJ, Chang CY, Koh HS, Jeon SH, Park EJ (2010) Galectin-3 exerts cytokine-like regulatory actions through the JAK-STAT pathway. Journal of immunology (Baltimore, Md : 1950) 185:7037-7046.
Karran E, Mercken M, De Strooper B (2011) The amyloid cascade hypothesis for Alzheimer`s disease: an appraisal for the development of therapeutics. Nature reviews Drug discovery 10:698-712.
Koo EH, Sisodia SS, Archer DR, Martin LJ, Weidemann A, Beyreuther K, Fischer P, Masters CL, Price DL (1990) Precursor of amyloid protein in Alzheimer disease undergoes fast anterograde axonal transport. Proceedings of the National Academy of Sciences of the United States of America 87:1561-1565.
Larson ME, Lesne SE (2012) Soluble Abeta oligomer production and toxicity. Journal of neurochemistry 120 Suppl 1:125-139.
Lashuel HA, Hartley D, Petre BM, Walz T, Lansbury PT, Jr. (2002) Neurodegenerative disease: amyloid pores from pathogenic mutations. Nature 418:291.
Lauren J, Gimbel DA, Nygaard HB, Gilbert JW, Strittmatter SM (2009) Cellular prion protein mediates impairment of synaptic plasticity by amyloid-beta oligomers. Nature 457:1128-1132.
Lee S, Fernandez EJ, Good TA (2007) Role of aggregation conditions in structure, stability, and toxicity of intermediates in the Aβ fibril formation pathway. Protein Science : A Publication of the Protein Society 16:723-732.
Li X, Zhang X, Ladiwala ARA, Du D, Yadav JK, Tessier PM, Wright PE, Kelly JW, Buxbaum JN (2013) Mechanisms of Transthyretin Inhibition of β-Amyloid Aggregation In Vitro. The Journal of neuroscience : the official journal of the Society for Neuroscience 33:19423-19433.
Liu B, Liao J, Rao X, Kushner SA, Chung CD, Chang DD, Shuai K (1998) Inhibition of Stat1-mediated gene activation by PIAS1. Proceedings of the National Academy of Sciences of the United States of America 95:10626-10631.
Liu B, Yang Y, Chernishof V, Loo RR, Jang H, Tahk S, Yang R, Mink S, Shultz D, Bellone CJ, Loo JA, Shuai K (2007) Proinflammatory stimuli induce IKKalpha-mediated phosphorylation of PIAS1 to restrict inflammation and immunity. Cell 129:903-914.
Liu FT, Rabinovich GA (2010) Galectins: regulators of acute and chronic inflammation. Annals of the New York Academy of Sciences 1183:158-182.
Liu FT, Patterson RJ, Wang JL (2002) Intracellular functions of galectins. Biochimica et biophysica acta 1572:263-273.
Luo Y, Vali S, Sun S, Chen X, Liang X, Drozhzhina T (2013) Aβ42-Binding Peptoids as Amyloid Aggregation. 4:952-962.
Ma T, Klann E (2012) Amyloid beta: linking synaptic plasticity failure to memory disruption in Alzheimer`s disease. Journal of neurochemistry 120 Suppl 1:140-148.
Magdesian MH, Carvalho MM, Mendes FA, Saraiva LM, Juliano MA, Juliano L, Garcia-Abreu J, Ferreira ST (2008) Amyloid-beta binds to the extracellular cysteine-rich domain of Frizzled and inhibits Wnt/beta-catenin signaling. The Journal of biological chemistry 283:9359-9368.
Maiolino G, Rossitto G, Pedon L, Cesari M, Frigo AC, Azzolini M, Plebani M, Rossi GP (2015) Galectin-3 predicts long-term cardiovascular death in high-risk patients with coronary artery disease. Arteriosclerosis, thrombosis, and vascular biology 35:725-732.
Maurer K, Volk S, Gerbaldo H (1997) Auguste D and Alzheimer`s disease. Lancet 349:1546-1549.
Nalivaeva NN, Belyaev ND, Zhuravin IA, Turner AJ (2012) The Alzheimer`s amyloid-degrading peptidase, neprilysin: can we control it? International journal of Alzheimer`s disease 2012:383796.
Reiman EM (2016) Alzheimer`s disease: Attack on amyloid-beta protein. Nature 537:36-37.
Roch JM, Masliah E, Roch-Levecq AC, Sundsmo MP, Otero DA, Veinbergs I, Saitoh T (1994) Increase of synaptic density and memory retention by a peptide representing the trophic domain of the amyloid beta/A4 protein precursor. Proceedings of the National Academy of Sciences of the United States of America 91:7450-7454.
Rotshenker S (2009) The role of Galectin-3/MAC-2 in the activation of the innate-immune function of phagocytosis in microglia in injury and disease. Journal of molecular neuroscience : MN 39:99-103.
Sato S, St-Pierre C, Bhaumik P, Nieminen J (2009) Galectins in innate immunity: dual functions of host soluble beta-galactoside-binding lectins as damage-associated molecular patterns (DAMPs) and as receptors for pathogen-associated molecular patterns (PAMPs). Immunological reviews 230:172-187.
Selkoe DJ (2001) Alzheimer`s disease: genes, proteins, and therapy. Physiological reviews 81:741-766.
Shankar GM, Bloodgood BL, Townsend M, Walsh DM, Selkoe DJ, Sabatini BL (2007) Natural oligomers of the Alzheimer amyloid-beta protein induce reversible synapse loss by modulating an NMDA-type glutamate receptor-dependent signaling pathway. The Journal of neuroscience : the official journal of the Society for Neuroscience 27:2866-2875.
Shin T (2013) The pleiotropic effects of galectin-3 in neuroinflammation: a review. Acta histochemica 115:407-411.
Spencer B, Desplats PA, Overk CR, Valera-Martin E, Rissman RA, Wu C, Mante M, Adame A, Florio J, Rockenstein E, Masliah E (2016) Reducing endogenous α-synuclein mitigates the degeneration of selective neuronal populations in an Alzheimer`s disease transgenic mouse model. The Journal of neuroscience : the official journal of the Society for Neuroscience 36:7971-7984.
Walsh DM, Klyubin I, Fadeeva JV, Cullen WK, Anwyl R, Wolfe MS, Rowan MJ, Selkoe DJ (2002) Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature 416:535-539.
Tai DJ, Hsu WL, Lin YC, Ma YL, Lee EH (2011) Novel role and mechanism of protein inhibitor of activated STAT1 in spatial learning. EMBO J 30(1):205-220
Wang J, Tan GJ, Han LN, Bai YY, He M, Liu HB (2017) Novel biomarkers for cardiovascular risk prediction. Journal of geriatric cardiology : JGC 14:135-150.
Wang X, Zhang S, Lin F, Chu W, Yue S (2015) Elevated galectin-3 levels in the serum of patients with Alzheimer`s disease. American journal of Alzheimer`s disease and other dementias 30:729-732.
Weingarten MD, Lockwood AH, Hwo SY, Kirschner MW (1975) A protein factor essential for microtubule assembly. Proceedings of the National Academy of Sciences of the United States of America 72:1858-1862.
Wyss-Coray T, Rogers J (2012) Inflammation in Alzheimer disease-a brief review of the basic science and clinical literature. Cold Spring Harbor perspectives in medicine 2(1):a006346.
Yan YP, Lang BT, Vemuganti R, Dempsey RJ (2009) Galectin-3 mediates post-ischemic tissue remodeling. Brain research 1288:116-124.
Zhao Q, Barclay M, Hilkens J, Guo X, Barrow H, Rhodes JM, Yu LG (2010) Interaction between circulating galectin-3 and cancer-associated MUC1 enhances tumour cell homotypic aggregation and prevents anoikis. Molecular cancer 9:154. |
| Description: | 碩士
國立政治大學
神經科學研究所
104754005 |
| Source URI: | http://thesis.lib.nccu.edu.tw/record/#G0104754005 |
| Data Type: | thesis |
| Appears in Collections: | [神經科學研究所] 學位論文
|
Files in This Item:
| File |
Size | Format | |
|---|
| 400501.pdf | 1294Kb | Adobe PDF2 | 722 | View/Open |
|
All items in 政大典藏 are protected by copyright, with all rights reserved.
|
