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研究生: 林德嫻
Lin, Te-Hsien
論文名稱: 中藥複方製劑芍藥甘草湯和Coumarin-chalcone衍生物在Tau蛋白易聚集表現之阿茲海默氏症細胞模式中之療效
Therapeutic Benefits of Formulated Chinese Medicine Shaoyao Gancao Tang and Coumarin-Chalcone Derivatives on Pro-aggregator Tau Induced Alzheimer's Disease Cell Models
指導教授: 李桂楨
Lee-Chen, Guey-Jen
口試委員: 陳瓊美 張國軒 李冠群 謝秀梅 李桂楨
口試日期: 2021/12/29
學位類別: 博士
Doctor
系所名稱: 生命科學系
Department of Life Science
論文出版年: 2022
畢業學年度: 110
語文別: 英文
論文頁數: 165
中文關鍵詞: 阿茲海默氏症Tau蛋白神經性發炎TRKB芍藥甘草湯Coumarin-chalcone衍生物
英文關鍵詞: Alzheimer's disease, Tau, neuroinflammation, TRKB, Shaoyao Gancao Tang, coumarin-chalcone derivatives
研究方法: 實驗設計法
DOI URL: http://doi.org/10.6345/NTNU202200064
論文種類: 學術論文
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  • 阿茲海默氏症(Alzheimer’s disease, AD)為一種進行性且不可逆的神經退化性疾病,受損的記憶和認知能力會逐漸失常最終造成身體功能的完全喪失。AD病人腦中最主要的特徵為不正常的Amyoild β與Tau蛋白聚集形成的老化斑塊(Senile plaque)和神經纖維纏結(Neurofibrillary tangles)。神經纖維纏結主要組成是高度磷酸化的Tau蛋白,而Tau蛋白的病變不僅在AD病人,也在許多Tauopathy中見到。在大腦中由於錯誤折疊形成的蛋白堆積,引發許多病理事件,例如氧化壓力、神經發炎,或是與神經細胞功能相關的訊息傳遞障礙,降低神經細胞存活。本篇研究主要是利用人類胚胎腎細胞HEK-293和神經纖維瘤母細胞SH-SY5Y,表現易聚集特性的ΔK280 TauRD片段蛋白,作為評估中藥製劑芍藥甘草湯(SG-Tang)以及Coumarin-chalcone衍生物LM-021、LM-031和LMDS-1~4化合物,抑制蛋白聚集、抗氧化和神經保護性的情形。芍藥甘草湯製劑,由甘草與白芍以等比例製成,除了可有效降低以LPS/IFN-γ刺激後活化的BV-2微膠細胞所釋出的NO、TNF-α、IL-1β及IL-6等前驅發炎細胞因子外,並可抑制由於誘導表現ΔK280 TauRD蛋白而上升的BAD、BID、CASP3、CASP8和CYCS表現,來達到Tau蛋白聚集抑制和神經保護性。其中LM-021除了本身有化學伴護活性可直接抑制ΔK280 TauRD的聚集外,還可透過PKA、CaMKII、ERK等路徑活化CREB和下游的BDNF、BCL2表現,來展現其神經保護之功能。接著在ΔK280 TauRD-DsRed SH-SY5Y細胞中,觀察到LM-031可提升HSPB1伴護蛋白表現以降低Tau蛋白的錯誤折疊,以及藉由活化NRF2/NQO1/GCLC和CREB調控之BDNF/AKT/ERK/BCL2路徑,來達到抑制細胞凋亡和促進細胞存活之效果。最後,因LM-031可提升CREB依存的BDNF表現,利用虛擬篩選找出LM-031類似化合物LMDS-1~4,並進一步以TRKB與ligand作用的d5-domain (PDB 1hcf),以分子模擬計算LM-031類似化合物與此蛋白片段的結合構形。細胞實驗結果顯示,LMDS-1和LMDS-2可經由TRKB/ERK和TRKB/PI3K/AKT訊息路徑,增加CREB磷酸化及其下游BDNF、BCL2基因表現。總結來說,本研究結果顯示芍藥甘草湯的抗氧化和抗發炎活性,可抑制神經細胞凋亡,在Tau蛋白聚集的細胞中展現其神經保護的能力,而Coumarin-chalcone衍生物LM-031、LM-021、LMDS-1、LMDS-2,具有活化HSPB1、NRF2及/或TRKB的作用,來降低Tau蛋白的錯誤摺疊、抑制細胞凋亡和促進神經細胞存活。以上這些研究結果顯示了芍藥甘草湯和Coumarin-chalcone衍生物,應用在AD治療上的潛能。

    Alzheimer’s disease (AD) is a progressive and irreversible neurodegenerative disease that affects memory and cognitive decline gradually and finally loss the ability in body motion. Unusual amyloid β protein aggregates and neurofibrillary tangles are found in the brains of AD patients. The neurofibrillary tangles are consisted of hyperphosphorylated Tau proteins, and this pathology hallmark exists in not only AD but also other tauopathies brains. The misfolded protein deposits cause series of events such as accumulation of oxidative stress, neuronal inflammation, and impairment of cell signaling to reduce neuronal survival. In this study pro-aggregator Tau (ΔK280 TauRD)-expressing human 293/SH-SY5Y cells were used to evaluate formulated Chinese herbal medicine Shaoyao Gancao Tang (SG-Tang) and coumarin-chalcone derivatives LM-021, LM-031 and LMDS-1~4 for their effects in anti-aggregative, anti-oxidative, and neuroprotective activities. SG-Tang, made of P. lactiflora and G. uralensis at 1:1 ratio), reduced NO, TNF-α, IL-1β and IL-6 in LPS/IFN-γ-activated mouse BV-2 microglia. Also, SG-Tang down-regulated BAD, BID, CASP3, CASP8 and CYCS expression for neuroprotection in ΔK280 TauRD-DsRed SH-SY5Y cells. The chemical chaperone activity of LM-021 inhibited ΔK280 TauRD aggregation in vitro. And LM-021 activated CREB-mediated BDNF and BCL2 gene expression through PKA, CaMKII and ERK for neuroprotection. In addition, another LM compound LM-031, not only upregulated HSPB1 chaperone to reduce Tau misfolding, but also activated NRF2/NQO1/GCLC and CREB-dependent BDNF/AKT/ERK/BCL2 pathways. Through these mechanisms, LM-031 suppress apoptosis and promote neuronal survival in ΔK280 TauRD-DsRed SH-SY5Y cells. As LM-031 upregulating CREB-dependent BDNF expression, virtual screening was conducted to obtain LM-031 analogs LMDS-1~4, followed by docking computation with TRKB d5 domain (PDB 1hcf). Among them, LMDS-1 and LMDS-2 activated TRKB/ERK and TRKB/PI3K/AKT signaling to increase CREB phosphorylation and downstream BDNF and BCL2 gene expression. In conclusion, SG-Tang displays neuroprotection by exerting anti-oxidative and anti-inflammatory activities to suppress neuronal apoptosis, and coumarin-chalcone derivatives LM-031, LM-021, LMDS-1 and LMDS-2 target HSPB1, NRF2 and/or TRKB to reduce Tau misfolding, suppress apoptosis and promote neuron survival. The study results shed light on the potential application of SG-Tang and these coumarin-chalcone derivatives in therapeutics of AD.

    謝辭 i 摘要 iii Abstract v Table of Contents vii Lists of Tables xii Lists of Figures xiii Chapter 1 Introduction 1 1.1 Neurodegenerative disorders 1 1.2 Alzheimer’s disease 2 1.2.1 Aging 3 1.2.2 Genetic factors 3 1.2.3 Acetylcholinesterase 6 1.3 Tau protein 7 1.3.1 Discover and category of Tau 7 1.3.2 Gene and isoforms of Tau 7 1.3.3 Structure of Tau 8 1.3.4 Function of Tau 9 1.3.5 Mutation of MAPT gene 11 1.3.6 Aggregation of Tau 12 1.3.7 Post-translational phosphorylation of Tau 12 1.4 Tau pathology 15 1.5 Molecular chaperones 16 1.6 Oxidative stress 18 1.7 NRF2 pathway and antioxidant 19 1.8 Neuroinflammation and apoptosis 20 1.9 CREB and BDNF/TRKB pathways 24 1.10 Therapeutic approaches for AD/tauopathy 28 1.10.1 Chinese herbal medicine (CHM) 28 1.10.2 Chalcones 30 1.10.3 Coumarins 31 1.10.4 Coumarin-chalcone hybrids 31 1.10.5 TRKB agonists 31 1.11 Tau cell model 32 1.12 Experimental aims 33 Chapter 2 Materials and methods 35 2.1. Tested herbal extracts 35 2.2. High performance liquid chromatography (HPLC) analysis of herbal extracts 35 2.3. Tested LM compounds 36 2.4. Bioavailability and BBB permeability prediction of LM compounds 36 2.5. Molecular modeling: docking computation 37 2.6. His-tagged wild type and ∆K280 TauRD construction and preparation 37 2.7. Anti-aggregation assay 38 2.8. Antioxidant activity assay 39 2.9. Cell culture 39 2.10. MTT cell viability assay 40 2.11. Nitric oxide (NO) detection and cytokine assays 40 2.12. Conditioned medium (CM) treatment 41 2.13. High content analysis of DsRed fluorescence 41 2.14. ROS assay 42 2.15. Real-time PCR analysis 43 2.16. High content analysis of neurite outgrowth 43 2.17. Lactate dehydrogenase (LDH) cytotoxicity assay 44 2.18. Caspase 3 (CASP3) activity assay 44 2.19. Caspase 1 (CASP1) activity assay 45 2.20. Acetylcholinesterase (AChE) activity assay 45 2.21. Genes knock-down by RNA-interference (RNAi) 45 2.22. Kinase inhibitor treatment 46 2.23. Immunoblotting assay 46 2.24. Parallel artificial membrane permeability assay (PAMPA) to assess BBB permeability 47 2.25. Statistical analysis 48 Chapter 3 Results 49 Section 1. Formulated Chinese medicine Shaoyao Gancao Tang reduces Tau aggregation and exerts neuroprotection through anti-oxidation and anti-inflammation 49 3.1. HPLC analysis of formulated CHMs 49 3.2 Cytotoxicity of formulated CHMs 49 3.3 Free radical scavenging activity of formulated CHMs 50 3.4. Anti-inflammatory activity of formulated CHMs in LPS-stimulated RAW 264.7 cells 50 3.5. Reduction of Tau misfolding and ROS of formulated CHMs in ΔK280 TauRD-DsRed 293 cells 50 3.6. Promotion of neurite outgrowth of SG-Tang in ΔK280 TauRD-DsRed SH-SY5Y cells 51 3.7. Anti-inflammatory effects of SG-Tang in LPS-stimulated BV-2 microglia 52 3.8. Effects of SG-Tang on BV-2 CM-inflamed ∆K280 TauRD-DsRed SH-SY5Y cells 53 3.9. Identification of SG-Tang targets in CM-inflamed ΔK280 TauRD-DsRed SH-SY5Y cells 54 Section 2. (E)-3-(3-(4-(dimethylamino)phenyl)acryloyl)-4-hydroxy-2H-chromen-2-one (LM-021) exhibits anti-aggregative and neuroprotective effects by up-regulating CREB signaling 56 3.10. Tested coumarin-chalcone compounds, free radical scavenging and biochemical Tau aggregation 56 3.11. Tests of coumarin-chalcone derivatives reducing Tau misfolding and ROS 56 3.12. Tests of coumarin-chalcone derivatives decreasing CASP1 activity and promoting neurite outgrowth 57 3.13. Regulation of CREB phosphorylation by LM-021 in ∆K280 TauRD-DsRed SH-SY5Y cells 57 Section 3. 3-Benzoyl-5-hydroxychromen-2-one (LM-031) reduces Tau aggregation and exerts neuroprotection through enhancing HSPB1 and NRF2, CREB pathways 60 3.14. Licochalcone A, synthetic LM compounds, and IC50 cytotoxicity 60 3.15. Anti-aggregation activity of licochalcone A and LM compounds on TauRD 60 3.16. Reduction of Tau misfolding and ROS of licochalcone A and LM compounds in ∆K280 TauRD-DsRed-expressing 293 cells 61 3.17. Promotion of neurite outgrowth of licochalcone A and LM-031 in ∆K280 TauRD-DsRed-expressing SH-SY5Y cells 61 3.18. Molecular targets of licochalcone A and LM-031 in ∆K280 TauRD-DsRed-expressing SH-SY5Y cells 62 3.19. NFR2 and CREB as therapeutic targets of LM-031 in ∆K280 TauRD-DsRed-expressing SH-SY5Y cells 63 Section 4. Novel TRKB agonists activate TRKB and downstream ERK and AKT signaling for neuroprotection 65 3.20. Test LM-031 and analogous compounds 65 3.21. Binding strength and conformation by docking computation 65 3.22. ∆K280 TauRD-DsRed aggregation inhibition and ROS reduction of LM-031 and analogs 66 3.23. CASP1 activity inhibition and neurite outgrowth promotion of LM-031 and analogs 66 3.24. TRKB expression and knockdown in ∆K280 TauRD-DsRed SH-SY5Y cells 67 3.25. Therapeutic targets of LMDS-1 and -2 in ∆K280 TauRD-DsRed SH-SY5Y cells 68 3.26. PAMPA to assess BBB permeability of LM-031, LMDS-1 and LMDS-2 69 Chapter 4 Discussion 71 4.1 CHM SG-Tang 72 4.2 LM-021 compound 74 4.3 LM-031 compound 77 4.4 LMDS compounds 78 4.5 General discussion 79 4.6 Conclusion 83 References 85

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