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 |
相關次數: | 點閱:143 下載:0 |
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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.
Abisambra JF, Blair LJ, Hill SE, Jones JR, Kraft C, Rogers J, Koren 3rd J, Jinwal UK, Lawson L, Johnson AG, et al. Phosphorylation dynamics regulate Hsp27-mediated rescue of neuronal plasticity deficits in Tau transgenic mice. J. Neurosci. 2010;30(46):15374-15382.
Aglah C, Gordon T, Posse de Chaves EI. cAMP promotes neurite outgrowth and extension through protein kinase A but independently of Erk activation in cultured rat motoneurons. Neuropharmacology 2008;55(1):8-17.
Allen M, Kachadoorian M, Quicksall Z, Zou F, Chai FH, Younkin C, Crook JE, Pankratz VS, Carrasquillo MM, Krishnan S, et al. Association of MAPT haplotypes with Alzheimer’s disease risk and MAPT brain gene expression levels. Alzheimers Res. Ther. 2014;6(4):39.
Alonso AC, Zaidi T, Novak M, Grundke-Iqbal I, Iqbal K. Hyperphosphorylation induces self-assembly of Tau into tangles of paired helical filaments/straight filaments. Proc. Natl. Acad. Sci. U. S. A. 2001;98(12):6923-6928.
Alonso AC, Li B, Grundke-Iqbal I, Iqbal K. Polymerization of hyperphosphorylated Tau into filaments eliminates its inhibitory activity. Proc. Natl. Acad. Sci. U. S. A. 2006;103(23):8864-8869.
Alzheimer A. About a peculiar disease of the cerebral cortex. By Alois Alzheimer, 1907 (Translated by L. Jarvik and H. Greenson). Alzheimer Dis. Assoc. Disord. 1987;1(1):3-8.
Amidfar M, de Oliveira J, Kucharska E, Budni J, Kim YK. The role of CREB and BDNF in neurobiology and treatment of Alzheimer’s disease. Life Sci. 2020;257:118020.
Arévalo JC, Wu SH. Neurotrophin signaling: many exciting surprises! Cell. Mol. Life Sci. 2006;63(13):1523-1537.
Arrasate M, Mitra S, Schweitzer ES, Segal MR, Finkbeiner S. Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death. Nature 2004;431(7010):805-810.
Atasoy İL, Dursun E, Gezen-Ak D, Metin-Armağan D, Öztürk M, Yılmazer S. Both secreted and the cellular levels of BDNF attenuated due to Tau hyperphosphorylation in primary cultures of cortical neurons. J. Chem. Neuroanat. 2017;80:19-26.
Avila Jesus, Lucas JJ, Perez M, Hernandez F. Role of Tau protein in both physiological and pathological conditions. Physiol. Rev. 2004;84(2):361-384.
Augustinack JC, Schneider A, Mandelkow EM, Hyman BT. Specific Tau phosphorylation sites correlate with severity of neuronal cytopathology in Alzheimer’s disease. Acta Neuropathol. 2002;103(1):26-35.
Bag S, Ghosh S, Tulsan R, Sood A, Zhou W, Schifone C, Foster M, LeVine 3rd H, Török B, Török M. Design, synthesis and biological activity of multifunctional α,β-unsaturated carbonyl scaffolds for Alzheimer’s disease. Bioorg. Med. Chem. Lett. 2013;23(9):2614-2618.
Bancher C, Brunner C, Lassmann H, Budka H, Jellinger K, Wiche G, Seitelberger F, Grundke-Iqbal I, Iqbal K, Wisniewski HM. Accumulation of abnormally phosphorylated Tau precedes the formation of neurofibrillary tangles in Alzheimer’s disease. Brain Res. 1989;477(1-2):90-99.
Banfield MJ, Naylor RL, Robertson AG, Allen SJ, Dawbarn D, Brady RL. Specificity in Trk receptor:neurotrophin interactions: the crystal structure of TrkB-d5 in complex with neurotrophin-4/5. Structure 2001;9(12):1191-1199.
Barbier P, Zejneli O, Martinho M, Lasorsa A, Belle V, Smet-Nocca C, Tsvetkov PO, Devred F, Landrieu I. Role of Tau as a microtubule-associated protein: Structural and functional aspects. Front. Aging Neurosci. 2019;11:204.
Bartolotti N, Bennett DA, Lazarov O. Reduced pCREB in Alzheimer’s disease prefrontal cortex is reflected in peripheral blood mononuclear cells. Mol. Psychiatry. 2016;21(9):1158-1166.
Baudier J, Cole RD. Interactions between the microtubule-associated Tau proteins and S100b regulate Tau phosphorylation by the Ca2+/calmodulin-dependent protein kinase II. J. Biol. Chem. 1988;263(12):5876-5883.
Baughman HER, Clouser AF, Klevit RE, Nath A. HspB1 and Hsc70 chaperones engage distinct Tau species and have different inhibitory effects on amyloid formation. J. Biol. Chem. 2018;293(8):2687-2700.
Baughman HER, Pham THT, Adams CS, Nath A, Klevit RE. Release of a disordered domain enhances HspB1 chaperone activity toward Tau. Proc. Natl. Acad. Sci. U. S. A. 2020;117(6):2923-2929.
Beach TG, Walker R, McGeer EG. Patterns of gliosis in Alzheimer’s disease and aging cerebrum. Glia 1989;2(6):420-436.
Bekris LM, Yu CE, Bird TD, Tsuang DW. Genetics of Alzheimer disease. J. Geriatr. Psychiatry Neurol. 2010;23(4):213-227.
Biancalana M, Koide S. Molecular mechanism of thioflavin-T binding to amyloid fibrils. Biochim. Biophys. Acta. 2010;1804(7):1405-1412.
Blurton-Jones M, Kitazawa M, Martinez-Coria H, Castello NA, Müller FJ, Loring JF, Yamasaki TR, Poon WW, Green KN, LaFerla FM. Neural stem cells improve cognition via BDNF in a transgenic model of Alzheimer disease. Proc. Natl. Acad. Sci. U. S. A. 2009;106(32):13594-13599.
Botez G, Probst A, Ipsen S, Tolnay M. Astrocytes expressing hyperphosphorylated Tau protein without glial fibrillary tangles in argyrophilic grain disease. Acta Neuropathol. 1999;98(3):251-256.
Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 1991;82(4):239-259.
Bradley MA , Xiong-Fister S, Markesbery WR, Lovell MA. Elevated 4-hydroxyhexenal in Alzheimer’s disease (AD) progression. Neurobiol. Aging 2012;33(6):1034-1044.
Brandt R, Léger J, Lee G. Interaction of Tau with the neural plasma membrane mediated by Tau’s amino-terminal projection domain. J. Cell Biol. 1995;131(5):1327-1340.
Breijyeh Z, Karaman R. Comprehensive review on Alzheimer’s disease: Causes and treatment. Molecules 2020;25(24):5789.
Buée L, Bussière T, Buée-Scherrer V, Delacourte A, Hof PR. Tau protein isoforms, phosphorylation and role in neurodegenerative disorders. Brain Res. Rev. 2000;33(1):95-130.
Bulic B, Pickhardt M, Schmidt B, Mandelkow EM, Waldmann H, Mandelkow E. Development of Tau aggregation inhibitors for Alzheimer’s disease. Angew. Chem. Int. Ed. Engl. 2009;48(10):1740-1752.
Burguillos MA, Deierborg T, Kavanagh E, Persson A, Hajji N, Garcia-Quintanilla A, Cano J, Brundin P, Englund E, Venero JL, et al. Caspase signalling controls microglia activation and neurotoxicity. Nature 2011;472(7343):319-324.
Butner KA, Kirschner MW. Tau protein binds to microtubules through a flexible array of distributed weak sites. J. Cell Biol. 1991;115(3):717-730.
Campanari ML, García-Ayllón MS, Blazquez-Llorca L, Luk WKW, Tsim K, Sáez-Valero J. Acetylcholinesterase protein level is preserved in the Alzheimer’s brain. J. Mol. Neurosci. 2014;53(3):446-453.
Campanari MT, Navarrete F, Ginsberg SD, Manzanares J, Sáez-Valero J, García-Ayllón MS. Increased expression of readthrough acetylcholinesterase variants in the brains of Alzheimer’s disease patients. J. Alzheimers Dis. 2016;53(3):831-841.
Cao LJ, Hou ZY, Li HD, Zhang BK, Fang PF, Xiang DX, Li ZH, Gong H, Deng Y, Ma YX, et al. The ethanol extract of Licorice (Glycyrrhiza uralensis) protects against triptolide-induced oxidative stress through activation of Nrf2. Evid. Based. Complement. Alternat. Med. 2017;2017:2752389.
Cash AD, Aliev G, Siedlak SL, Nunomura A, Fujioka H, Zhu X, Raina AK, Vinters HV, Tabaton M, Johnson AB, et al. Microtubule reduction in Alzheimer’s disease and aging is independent of Tau filament formation. Am. J. Pathol. 2003;162(5):1623-1627.
Cente M, Filipcik P, Pevalova M, Novak M. Expression of a truncated Tau protein induces oxidative stress in a rodent model of tauopathy. Eur. J. Neurosci. 2006;24(4):1085-1090.
Chang KH, Chen IC, Lin HY, Chen HC, Lin CH, Lin TH, Weng YT, Chao CY, Wu YR, Lin JY, et al. The aqueous extract of Glycyrrhiza inflata can upregulate unfolded protein response-mediated chaperones to reduce Tau misfolding in cell models of Alzheimer’s disease. Drug Des. Devel. Ther. 2016;10:885-896.
Chang KH, Lin CH, Chen HC, Huang HY, Chen SL, Lin TH, Ramesh C, Huang CC, Fung HC, Wu YR, et al. The Potential of indole/indolylquinoline compounds in Tau misfolding reduction by enhancement of HSPB1. CNS Neurosci. Ther. 2017;23(1):45-56.
Chaudhary RK, Patel KA, Patel MK, Joshi RH, Roy I. Inhibition of aggregation of mutant huntingtin by nucleic acid aptamers in vitro and in a yeast model of Huntington's disease. Mol. Ther. 2015;23(12):1912-1926.
Chen J, Kanai Y, Cowan NJ, Hirokawa N. Projection domains of MAP2 and Tau determine spacings between microtubules in dendrites and axons. Nature 1992;360(6405):674-677.
Chen LQ, Wei JS, Lei ZN, Zhang LM, Liu Y, Sun FY. Induction of Bcl-2 and Bax was related to hyperphosphorylation of Tau and neuronal death induced by okadaic acid in rat brain. Anat. Rec. A Discov. Mol. Cell. Evol. Biol. 2005;287(2):1236-1245.
Chen SY, Gao Y, Sun JY, Meng XL, Yang D, Fan LH, Xiang L, Wang P. Traditional Chinese medicine: Role in reducing β-amyloid, apoptosis, autophagy, neuroinflammation, oxidative stress, and mitochondrial dysfunction of Alzheimer’s disease. Front. Pharmacol. 2020;2;11:497.
Cheng Y and Bai F. The association of Tau with mitochondrial dysfunction in Alzheimer’s disease. Front. Neurosci. 2018;12:163.
Chitranshi N, Gupta V, Kumar S, Graham SL. Exploring the molecular interactions of 7,8-dihydroxyflavone and its derivatives with TrkB and VEGFR2 proteins. Int. J. Mol. Sci. 2015;16(9):21087-21108.
Chiu YJ, Lin TH, Chen CM, Lin CH, Teng YS, Lin CY, Sun YC, Hsieh-Li HM, Su MT, Lee-Chen GJ, et al. Novel synthetic coumarin-chalcone derivative (E)-3-(3-(4-(dimethylamino)phenyl)acryloyl)-4-hydroxy-2H-chromen-2-one activates CREB-mediated neuroprotection in Aβ and Tau cell models of Alzheimer’s disease. Oxid. Med. Cell. Longev. 2021;2021:3058861.
Chohan MO, Haque N, Alonso A, El-Akkad E, Grundke-Iqbal I, Grover A, Iqbal K. Hyperphosphorylation-induced self assembly of murine Tau: a comparison with human Tau. J. Neural. Transm. (Vienna) 2005;112(8):1035-1047.
Cleveland DW, Hwo SY, Kirschner MW. Physical and chemical properties of purified Tau factor and the role of Tau in microtubule assembly. J. Mol. Biol. 1977;116(2):227-247.
Connor B, Young D, Yan Q, Faull RL, Synek B, Dragunow M. Brain-derived neurotrophic factor is reduced in Alzheimer’s disease. Brain Res. Mol. Brain Res. 1997;49(1-2):71-81.
Cortés N, Andrade V, Guzmán-Martínez L, Estrella M, Maccioni RB. Neuroimmune Tau mechanisms: Their role in the progression of neuronal degeneration. Int. J. Mol. Sci. 2018;19(4):956.
Cortés-Gómez MA, Llorens-Álvarez E, Alom J, Del Ser T, Avila J, Sáez-Valero J, García-Ayllón MS. Tau phosphorylation by glycogen synthase kinase 3β modulates enzyme acetylcholinesterase expression. J. Neurochem. 2021;157(6):2091-2105.
Cotman CW, Poon WW, Rissman RA, Blurton-Jones M. The role of caspase cleavage of Tau in Alzheimer disease neuropathology. J. Neuropathol. Exp. Neurol. 2005;64(2):104-112.
Cowan CM, Mudher A. Are Tau aggregates toxic or protective in tauopathies? Front. Neurol. 2013;4:114.
Cruz JC, Tseng HC, Goldman JA, Shih H, Tsai LH. Aberrant Cdk5 activation by p25 triggers pathological events leading to neurodegeneration and neurofibrillary tangles. Neuron 2003;40(3):471-483.
Cuadrado A, Manda G, Hassan A, Alcaraz MJ, Barbas C, Daiber A, Ghezzi P, León R, López MG, Oliva B, et al. Transcription factor NRF2 as a therapeutic target for chronic diseases: A systems medicine approach. Pharmacol. Rev. 2018;70(2):348-383.
Cuchillo-Ibanez I, Seereeram A, Byers HL, Leung KY, Ward MA, Anderton BH, Hanger DP. Phosphorylation of Tau regulates its axonal transport by controlling its binding to kinesin. FASEB J. 2008 Sep;22(9):3186-3195.
Cunha C, Brambilla R, Thomas KL. A simple role for BDNF in learning and memory? Front. Mol. Neurosci. 2010;3:1.
Dash PK, Karl KA, Colicos MA, Prywes R, Kandel ER. cAMP response element-binding protein is activated by Ca2+/calmodulin- as well as cAMP-dependent protein kinase. Proc. Natl. Acad. Sci U S A. 1991;88(11):5061-5065.
Davies DA, Adlimoghaddam A, Albensi BC. Role of Nrf2 in synaptic plasticity and memory in Alzheimer’s disease. Cells 2021;10(8):1884.
David DC, Hauptmann S, Scherping I, Schuessel K, Keil U, Rizzu P, Ravid R, Dröse S, Brandt U, Müller WE, et al. Proteomic and functional analyses reveal a mitochondrial dysfunction in P301L Tau transgenic mice. J. Biol. Chem. 2005;280(25):23802-23814.
Dawson HN, Cantillana V, Jansen M, Wang H, Vitek MP, Wilcock DM, Lynch JR, Laskowitz DT. Loss of Tau elicits axonal degeneration in a mouse model of Alzheimer’s disease. Neuroscience 2010;169(1):516-531.
de Souza LG, Rennã MN, Figueroa-Villar JD. Coumarins as cholinesterase inhibitors: A review. Chem. Biol. Interact. 2016;254:11-23.
De Strooper B, Annaert W. Novel research horizons for presenilins and γ-secretases in cell biology and disease. Annu. Rev. Cell Dev. Biol. 2010;26:235-260.
Dehmelt L, Halpain S. The MAP2/Tau family of microtubule-associated proteins. Genome Biol. 2005;6(1):204.
Delisle MB, Murrell JR, Richardson R, Trofatter JA, Rascol O, Soulages X, Mohr M, Calvas P, Ghetti B. A mutation at codon 279 (N279K) in exon 10 of the Tau gene causes a tauopathy with dementia and supranuclear palsy. Acta Neuropathol. 1999;98(1):62-77.
Desikan RS, Schork AJ, Wang Y, Witoelar A, Sharma M, McEvoy LK, Holland D, Brewer JB, Chen CH, Thompson WK, et al. Genetic overlap between Alzheimer’s disease and Parkinson’s disease at the MAPT locus. Mol. Psychiatry. 2015;20(12):1588-1595.
DeVos SL, Hyman BT. Tau at the crossroads between neurotoxicity and neuroprotection. Neuron 2017;94(4):703-704.
Di L, Kerns EH, Fan K, McConnell OJ, Carter GT. High throughput artificial membrane permeability assay for blood-brain barrier. Eur. J. Med. Chem. 2003;38(3):223-232.
Di L, Kerns EH, Bezar IF, Petusky SL, Huang Y. Comparison of blood-brain barrier permeability assays: in situ brain perfusion, MDR1-MDCKII and PAMPA-BBB. J. Pharm. Sci. 2009;98(6):1980–1991.
Dias-Santagata D, Fulga TA, Duttaroy A, Feany MB. Oxidative stress mediates Tau-induced neurodegeneration in Drosophila. J. Clin. Invest. 2007;117(1):236-245.
DiSabato DJ, Quan N, Godbout JP. Neuroinflammation: the devil is in the details. J. Neurochem. 2016;139(Suppl 2):136-153.
Drewes G, Ebneth A, Preuss U, Mandelkow EM, Mandelkow E. MARK, a novel family of protein kinases that phosphorylate microtubule-associated proteins and trigger microtubule disruption. Cell 1997;89(2):297-308.
D’Souza I, Poorkaj P, Hong M, Nochlin D, Lee VM, Bird TD, Schellenberg GD. Missense and silent Tau gene mutations cause frontotemporal dementia with parkinsonism-chromosome 17 type, by affecting multiple alternative RNA splicing regulatory elements. Proc. Natl. Acad. Sci. U. S. A. 1999;96(10):5598-5603.
D’Souza I, Schellenberg GD. Determinants of 4-repeat Tau expression. Coordination between enhancing and inhibitory splicing sequences for exon 10 inclusion. J. Biol. Chem. 2000;275(23):17700-17709.
Du X, Wang X, Geng M. Alzheimer’s disease hypothesis and related therapies. Transl. Neurodegener. 2018;7:2.
Dugger BN, Dickson DW. Pathology of neurodegenerative diseases. Cold Spring Harb. Perspect. Biol. 2017;9(7):a028035.
Dujardin S, Hyman BT. Tau prion-like propagation: State of the art and current challenges. Adv. Exp. Med. Biol. 2019;1184:305-325.
Dumont M, Stack C, Elipenahli C, Jainuddin S, Gerges M, Starkova NN, Yang L, Starkov AA, Beal F. Behavioral deficit, oxidative stress, and mitochondrial dysfunction precede Tau pathology in P301S transgenic mice. FASEB J. 2011;25(11):4063-4072.
Ebneth A, Godemann R, Stamer K, Illenberger S, Trinczek B, Mandelkow E. Overexpression of Tau protein inhibits kinesin-dependent trafficking of vesicles, mitochondria, and endoplasmic reticulum: implications for Alzheimer’s disease. J. Cell Biol. 1998;143(3):777-794.
Eckermann K, Mocanu MM, Khlistunova I, Biernat J, Nissen A, Hofmann A, Schönig K, Bujard H, Haemisch A, Mandelkow E, et al. The β-propensity of Tau determines aggregation and synaptic loss in inducible mouse models of tauopathy. J. Biol. Chem. 2007;282(43):31755-31765.
Eckman CB, Mehta ND, Crook R, Perez-tur J, Prihar G, Pfeiffer E, Graff-Radford N, Hinder P, Yager D, Zenk B, et al. A new pathogenic mutation in the APP gene (I716V) increases the relative proportion of Aβ42(43). Hum. Mol. Genet. 1997;6(12):2087-2089.
Elliott E, Atlas R, Lange A, Ginzburg I. Brain-derived neurotrophic factor induces a rapid dephosphorylation of Tau protein through a PI-3 Kinase signalling mechanism. Eur. J. Neurosci. 2005;22(5):1081-1089.
Fang H, Pengal RA, Cao X, Ganesan LP, Wewers MD, Marsh CB, Tridandapani S. Lipopolysaccharide-induced macrophage inflammatory response is regulated by SHIP. J. Immunol. 2004;173(1):360-366.
Feliciello A, Gottesman ME, Avvedimento EV. The biological functions of A-kinase anchor proteins. J. Mol. Biol. 2001;308(2):99-114.
Flores J, Noël A, Foveau B, Lynham J, Lecrux C, LeBlanc AC. Caspase-1 inhibition alleviates cognitive impairment and neuropathology in an Alzheimer’s disease mouse model. Nat. Commun. 2018;9(1):3916.
Frid P, Anisimov SV, Popovic N. Congo red and protein aggregation in neurodegenerative diseases. Brain Res. Rev. 2007;53(1):135-160.
Frost B, Diamond MI. Prion-like mechanisms in neurodegenerative diseases. Nat. Rev. Neurosci. 2010;11(3):155-159.
Fujio K, Sato M, Uemura T, Sato T, Sato-Harada R, Harada A. 14-3-3 proteins and protein phosphatases are not reduced in Tau-deficient mice. Neuroreport 2007;18(10):1049-1052.
Fyffe-Maricich SL, Karlo JC, Landreth GE, Miller RH. The ERK2 mitogen-activated protein kinase regulates the timing of oligodendrocyte differentiation. J. Neurosci. 2011;31(3):843-850.
Gamblin TC, Chen F, Zambrano A, Abraha A, Lagalwar S, Guillozet AL, Lu M, Fu Y, Garcia-Sierra F, LaPointe N, et al. Caspase cleavage of Tau: Linking amyloid and neurofibrillary tangles in Alzheimer’s disease. Proc. Natl. Acad. Sci. U. S. A. 2003;100(17):10032-10037.
Gao L, Tian M, Zhao HY, Xu QQ, Huang YM, Si QC, Tian Q, Wu QM, Hu XM, Sun LB, McClintock SM, Zeng Y. TrkB activation by 7, 8-dihydroxyflavone increases synapse AMPA subunits and ameliorates spatial memory deficits in a mouse model of Alzheimer’s disease. J. Neurochem. 2016;136(3):620-636.
Garwood CJ, Cooper JD, Hanger DP, Noble W. Anti-inflammatory impact of minocycline in a mouse model of tauopathy. Front. Psychiatry. 2010;1:136.
Genovese T, Menegazzi M, Mazzon E, Crisafulli C, Di Paola R, Dal Bosco M, Zou Z, Suzuki H, Cuzzocrea S. Glycyrrhizin reduces secondary inflammatory process after spinal cord compression injury in mice. Shock 2009;31(4):367-375.
Georgieff IS, Liem RK, Couchie D, Mavilia C, Nunez J, Shelanski ML. Expression of high molecular weight Tau in the central and peripheral nervous systems. J. Cell Sci. 1993;105(3):729-737.
Ginsberg SD, Malek-Ahmadi MH, Alldred MJ, Che S, Elarova I, Chen Y, Jeanneteau F, Kranz TM, Chao MV, Counts SE, et al. Selective decline of neurotrophin and neurotrophin receptor genes within CA1 pyramidal neurons and hippocampus proper: Correlation with cognitive performance and neuropathology in mild cognitive impairment and Alzheimer’s disease. Hippocampus 2019;29(5):422-439.
Goate A, Chartier-Harlin MC, Mullan M, Brown J, Crawford F, Fidani L, Giuffra L, Haynes A, Irving N, James L, et al. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease. Nature 1991;349(6311):704-706.
Goedert M, Spillantini MG, Jakes R, Rutherford D, Crowther RA. Multiple isoforms of human microtubule-associated protein Tau: sequences and localization in neurofibrillary tangles of Alzheimer’s disease. Neuron 1989;3(4):519-526.
Gong H, Zhang BK, Yan M, Fang PF, Li HD, Hu HP, Yang Y, Cao P, Jiang P, Fan XR. A protective mechanism of licorice (Glycyrrhiza uralensis): isoliquiritigenin stimulates detoxification system via Nrf2 activation. J. Ethnopharmacol. 2015;162:134-139.
Gonzalez GA, Montminy MR. Cyclic AMP stimulates somatostatin gene transcription by phosphorylation of CREB at serine 133. Cell 1989;59(4):675-680.
González-Reyes S, Guzmán-Beltrán S, Medina-Campos ON, Pedraza-Chaverri J. Curcumin pretreatment induces Nrf2 and an antioxidant response and prevents hemin-induced toxicity in primary cultures of cerebellar granule neurons of rats. Oxid. Med. Cell. Longev. 2013;2013:801418.
Goode BL, Chau M, Denis PE, Feinstein SC. Structural and functional differences between 3-repeat and 4-repeat Tau isoforms. Implications for normal Tau function and the onset of neurodegenetative disease. J. Biol. Chem. 2000;275(49):38182-38189.
Graham RK, Ehrnhoefer DE, Hayden MR. Caspase-6 and neurodegeneration. Trends Neurosci. 2011;34(12):646-656.
Grewal SS, York RD, Stork PJ. Extracellular-signal-regulated kinase signalling in neurons. Curr. Opin. Neurobiol. 1999;9(5):544-553.
Grundke-Iqbal I, Iqbal K, Tung YC, Quinlan M, Wisniewski HM, Binder LI. Abnormal phosphorylation of the microtubule-associated protein Tau (Tau) in Alzheimer cytoskeletal pathology. Proc. Natl. Acad. Sci. U. S. A. 1986;83(13):4913-4917.
Guo H, Albrecht S, Bourdeau M, Petzke T, Bergeron C, LeBlanc AC. Active caspase-6 and caspase-6-cleaved Tau in neuropil threads, neuritic plaques, and neurofibrillary tangles of Alzheimer’s disease. Am. J. Pathol. 2004;165(2):523-531.
Gustke N, Trinczek B, Biernat J, Mandelkow EM, Mandelkow E. Domains of Tau protein and interactions with microtubules. Biochemistry 1994;33(32):9511-9522.
Guzman-Martinez L, Maccioni RB, AndradeV, Navarrete LP , Pastor MG, Ramos-Escobar N. Neuroinflammation as a common feature of neurodegenerative disorders. Front. Pharmacol. 2019;10:1008.
Hampel H, Mesulam MM, Cuello AC, Farlow MR, Giacobini E, Grossberg GT, Khachaturian AS, Vergallo A, Cavedo E, Snyder PJ, et al. The cholinergic system in the pathophysiology and treatment of Alzheimer’s disease. Brain 2018;141(7):1917-1933.
Han JH, Park J, Kang TB, Lee KH. Regulation of caspase-8 activity at the crossroads of pro-inflammation and anti-inflammation. Int. J. Mol. Sci. 2021;22(7):3318.
Hanger DP, Betts JC, Loviny TL, Blackstock WP, Anderton BH. New phosphorylation sites identified in hyperphosphorylated Tau (paired helical filament-Tau) from Alzheimer’s disease brain using nanoelectrospray mass spectrometry. J. Neurochem. 1998;71(6):2465-7246.
Hanger DP, Anderton BH, Noble W. Tau phosphorylation: The therapeutic challenge for neurodegenerative disease. Trends Mol. Med. 2009;15(3):112-119.
Hanisch UK. Microglia as a source and target of cytokines. Glia 2002;40(2):140-155.
Hanslik KL, Ulland TK. The role of microglia and the Nlrp3 inflammasome in Alzheimer’s disease. Front. Neurol. 2020;11:570711.
Hanson PI, Schulman H. Neuronal Ca2+/calmodulin-dependent protein kinases. Annu. Rev. Biochem. 1992;61:559-601.
Harada A, Oguchi K, Okabe S, Kuno J, Terada S, Ohshima T, Sato-Yoshitake R, Takei Y, Noda T, Hirokawa N. Altered microtubule organization in small-calibre axons of mice lacking Tau protein. Nature 1994;369(6480):488-491.
Hartl FU, Bracher A, Hayer-Hartl M. Molecular chaperones in protein folding and proteostasis. Nature 2011;475(7356):324-332.
Hasegawa M, Morishima-Kawashima M, Takio K, Suzuki M, Titani K, Ihara Y. Protein sequence and mass spectrometric analyses of Tau in the Alzheimer’s disease brain. J. Biol. Chem. 1992;267(24):17047-17054.
Haslbeck M, Vierling E. A first line of stress defense: small heat shock proteins and their function in protein homeostasis. J. Mol. Biol. 2015;427(7):1537-1548.
Hassanein EHM, Sayed AM, Hussein OE, Mahmoud AM. Coumarins as modulators of the Keap1/Nrf2/ARE signaling pathway. Oxid. Med. Cell. Longev. 2020 Apr 22;2020:1675957.
Heneka MT, McManus RM, Latz E. Inflammasome signalling in brain function and neurodegenerative disease. Nat. Rev. Neurosci. 2018;19(10):610-621.
Hirokawa N, Shiomura Y, Okabe S. Tau proteins: the molecular structure and mode of binding on microtubules. J. Cell Biol. 1988;107(4):1449-1459.
Ho YS, So KF, Chang RCC. Drug discovery from Chinese medicine against neurodegeneration in Alzheimer’s and vascular dementia. Chin. Med. 2011;6:15.
Hong M, Zhukareva V, Vogelsberg-Ragaglia V, Wszolek Z, Reed L, Miller BI, Geschwind DH, Bird TD, McKeel D, Goate A, et al. Mutation-specific functional impairments in distinct Tau isoforms of hereditary FTDP-17. Science 1998;282(5395):1914-1917.
Hoover BR, Reed MN, Su J, Penrod RD, Kotilinek LA, Grant MK, Pitstick R, Carlson GA, Lanier LM, Yuan LL, et al. Tau mislocalization to dendritic spines mediates synaptic dysfunction independently of neurodegeneration. Neuron 2010;68(6):1067-1081.
Hutton M, Lendon CL, Rizzu P, Baker M, Froelich S, Houlden H, Pickering-Brown S, Chakraverty S, Isaacs A, Grover A, et al. Association of missense and 5’-splice-site mutations in Tau with the inherited dementia FTDP-17. Nature 1998;393(6686):702-705.
Hwang SC, Jhon DY, Bae YS, Kim JH, Rhee SG. Activation of phospholipase C-γ by the concerted action of Tau proteins and arachidonic acid. J. Biol. Chem. 1996;271(31):18342-18349.
Idrees M, Khan S, Memon NH, Zhang Z. Effect of the phytochemical agents against the SARS-CoV and some of them selected for application to COVID-19: A mini-review. Curr. Pharm. Biotechnol. 2021;22(4):444-450.
Ikegami S, Harada A, Hirokawa N. Muscle weakness, hyperactivity, and impairment in fear conditioning in Tau-deficient mice. Neurosci. Lett. 2000;279(3):129-132.
Iqbal K, Alonso AC, Grundke-Iqbal I. Cytosolic abnormally hyperphosphorylated Tau but not paired helical filaments sequester normal MAPs and inhibit microtubule assembly. J. Alzheimers Dis. 2008;14(4):365-370.
Iqbal K, Liu F, Gong CX, Grundke-Iqbal I. Tau in Alzheimer disease and related tauopathies. Curr. Alzheimer Res. 2010;7(8):656-664.
Ising C, Venegas C, Zhang S, Scheiblich H, Schmidt SV, Vieira-Saecker A, Schwartz S, Albasset S, McManus RM, Tejera D, et al. NLRP3 inflammasome activation drives Tau pathology. Nature 2019;575(7784):669-673.
Itagaki S, McGeer PL, Akiyama H, Zhu S, Selkoe D. Relationship of microglia and astrocytes to amyloid deposits of Alzheimer disease. J. Neuroimmunol. 1989;24(3):173-182.
Jang SW, Liu X, Yepes M, Shepherd KR, Miller GW, Liu Y, Wilson WD, Xiao G, Blanchi B, Sun YE, et al. A selective TrkB agonist with potent neurotrophic activities by 7,8-dihydroxyflavone. Proc. Natl. Acad. Sci. U. S. A. 2010;107(6):2687-2692.
Jang YJ, Syu SE, Chen YJ, Yang MC, Lin W. Syntheses of furo[3,4-c]coumarins and related furyl coumarin derivatives via intramolecular Wittig reactions. Org. Biomol. Chem. 2012;10(4):843-847.
Jaunmuktane Z, Brandner S. Invited review: The role of prion-like mechanisms in neurodegenerative diseases. Neuropathol. Appl. Neurobiol. 2020;46(6):522-545.
Jeganathan S, von Bergen M, Brutlach H, Steinhoff HJ, Mandelkow E. Global hairpin folding of Tau in solution. Biochemistry 2006;45(7):2283-2293.
Jiang H, Li J, Wang L, Wang S, Nie X, Chen Y, Fu Q, Jiang M, Fu C, He Y. Total glucosides of paeony: A review of its phytochemistry, role in autoimmune diseases, and mechanisms of action. J. Ethnopharmacol. 2020a;258:112913.
Jiang M, Zhao S, Yang S, Lin X, He X, Wei X, Song Q, Li R, Fu C, Zhang J, et al. An "essential herbal medicine"-licorice: A review of phytochemicals and its effects in combination preparations. J. Ethnopharmacol. 2020b;249:112439.
Jiang X, Chai GS, Wang ZH, Hu Y, Li XG, Ma ZW, Wang Q, Wang JZ, Liu GP. Spatial training preserves associative memory capacity with augmentation of dendrite ramification and spine generation in Tg2576 mice. Sci. Rep. 2015;5:9488.
Jicha GA, Weaver C, Lane E, Vianna C, Kress Y, Rockwood J, Davies P. cAMP-dependent protein kinase phosphorylations on Tau in Alzheimer’s disease. J. Neurosci. 1999;19(17):7486-7494.
Jo C, Gundemir S, Pritchard S, Jin YN, Rahman I, Johnson GVW. Nrf2 reduces levels of phosphorylated Tau protein by inducing autophagy adaptor protein NDP52. Nat. Commun. 2014;5:3496.
Johannessen M, Moens U. Multisite phosphorylation of the cAMP response element-binding protein (CREB) by a diversity of protein kinases. Front. Biosci. 2007;12:1814-1832.
Johnson DA, Johnson JA. Nrf2--a therapeutic target for the treatment of neurodegenerative diseases. Free Radic. Biol. Med. 2015;88(Pt B):253-267.
Kansy M, Senner F, Gubernator K. Physicochemical high throughput screening: parallel artificial membrane permeation assay in the description of passive absorption processes. J. Med. Chem. 1998;41(7):1007-1010.
Kaushal V, Dye R, Pakavathkumar P, Foveau B, Flores J, Hyman B, Ghetti B, Koller BH, LeBlanc AC. Neuronal NLRP1 inflammasome activation of Caspase-1 coordinately regulates inflammatory interleukin-1-beta production and axonal degeneration-associated Caspase-6 activation. Cell Death Differ. 2015;22(10):1676-1686.
Ke YD, Suchowerska AK, van der Hoven J, De Silva DM, Wu CW, van Eersel J, Ittner A, Ittner LM. Lessons from Tau-deficient mice. Int. J. Alzheimers Dis. 2012;2012:873270.
Kelleher 3rd RJ, Shen J. Presenilin-1 mutations and Alzheimer’s disease. Proc. Natl. Acad. Sci. U. S. A. 2017;114(4):629-631.
Kellogg EH, Hejab NMA, Poepsel S, Downing KH, DiMaio F, Nogales E. Near-atomic model of microtubule-Tau interactions. Science 2018;360(6394):1242-1246.
Khlistunova I, Biernat J, Wang Y, Pickhardt M, von Bergen M, Gazova Z, Mandelkow E, Mandelkow EM. Inducible expression of Tau repeat domain in cell models of tauopathy: aggregation is toxic to cells but can be reversed by inhibitor drugs. J. Biol. Chem. 2006;281(2):1205-1214.
Kim J, Basak JM, Holtzman DM. The role of apolipoprotein E in Alzheimer’s disease. Neuron 2009;63(3):287-303.
Kim JY, Park SJ, Yun KJ, Cho YW, Park HJ, Lee KT. Isoliquiritigenin isolated from the roots of Glycyrrhiza uralensis inhibits LPS-induced iNOS and COX-2 expression via the attenuation of NF-κB in RAW 264.7 macrophages. Eur. J. Pharmacol. 2008;584(1):175-184.
Kimura T, Ono T, Takamatsu J, Yamamoto H, Ikegami K, Kondo A, Hasegawa M, Ihara Y, Miyamoto E, Miyakawa T. Sequential changes of Tau-site-specific phosphorylation during development of paired helical filaments. Dementia 1996;7(4):177-181.
Köpke E, Tung YC, Shaikh S, Alonso AC, Iqbal K, Grundke-Iqbal I. Microtubule-associated protein Tau. Abnormal phosphorylation of a non-paired helical filament pool in Alzheimer disease. J. Biol. Chem. 1993;268(32):24374-14384.
Kühnl J, Roggenkamp D, Gehrke SA, Stäb F, Wenck H, Kolbe L, Neufang G. Licochalcone A activates Nrf2 in vitro and contributes to licorice extract-induced lowered cutaneous oxidative stress in vivo. Exp. Dermatol. 2015;24(1):42-47.
Law BYK, Wu AG, Wang MJ, Zhu YZ. Chinese medicine: A hope for neurodegenerative diseases? J. Alzheimers Dis. 2017;60(s1):S151-S160.
Le Corre S, Klafki HW, Plesnila N, Hübinger G, Obermeier A, Sahagún H, Monse B, Seneci P, Lewis J, Eriksen J, et al. An inhibitor of Tau hyperphosphorylation prevents severe motor impairments in Tau transgenic mice. Proc. Natl. Acad. Sci. U. S. A. 2006;103(25):9673-9678.
LeBlanc AC. Novel therapeutic target against Alzheimer. Oncotarget 2017;8(30):48529-48530.
Lebouvier T, Scales TME, Hanger DP, Geahlen RL, Lardeux B, Reynolds CH, Anderton BH, Derkinderen P. The microtubule-associated protein Tau is phosphorylated by Syk. Biochim. Biophys. Acta. 2008;1783(2):188-192.
Lee CJ, Tsai CC, Hong SH, Chang GH, Yang MC, Möhlmann L., Lin W. Preparation of furo[3,2-c]coumarins from 3-cinnamoyl-4-hydroxy-2H-chromen-2-ones and acyl chlorides: a bu3P-mediated C-acylation/cyclization sequence. Angew Chem. Int. Ed. Engl. 2015;54(29):8502-8505.
Lee B, Sur B, Cho SG, Yeom M, Shim I, Lee H, Hahm DH. Wogonin attenuates hippocampal neuronal loss and cognitive dysfunction in trimethyltin-intoxicated rats. Biomol. Ther. (Seoul) 2016;24(3):328-337.
Lee G, Newman ST, Gard DL, Band H, Panchamoorthy G. Tau interacts with src-family non-receptor tyrosine kinases. J. Cell Sci. 1998;111(21):3167-3177.
Lee G, Thangavel R, Sharma VM, Litersky JM, Bhaskar K, Fang SM, Do LH, Andreadis A, Van Hoesen G, Ksiezak-Reding H. Phosphorylation of Tau by fyn: implications for Alzheimer’s disease J. Neurosci. 2004;24(9):2304-2312.
Lee SY, Chiu YJ, Yang SM, Chen CM, Huang CC, Lee-Chen GJ, Lin W, Chang KH. Novel synthetic chalcone-coumarin hybrid for Aβ aggregation reduction, antioxidation, and neuroprotection. CNS Neurosci. Ther. 2018;24(12):1286-1298.
Lee YT, Jang YJ, Syu SE, Chou SC, Lee CJ, Lin W. Preparation of functional benzofurans and indoles via chemoselective intramolecular Wittig reactions. Chem. Commun. 2012;48(65):8135-8137.
Lei P, Ayton S, Finkelstein DI, Spoerri L, Ciccotosto GD, Wright DK, Wong BXW, Adlard PA, Cherny RA, Lam LQ, et al. Tau deficiency induces parkinsonism with dementia by impairing APP-mediated iron export. Nat. Med. 2012;18(2):291-295.
Leng F, Edison P. Neuroinflammation and microglial activation in Alzheimer disease: where do we go from here? Nat. Rev. Neurol. 2021;17(3):157-172.
Lévy E, El Banna N, Baïlle D, Heneman-Masurel A , Truchet S, Rezaei H, Huang ME, Béringue V, Martin D, Vernis L. Causative links between protein aggregation and oxidative stress: A Review. Int. J. Mol. Sci. 2019;20(16):3896.
Li SL, Song JZ, Choi FFK, Qiao CF, Zhou Y, Han QB, Xu HX. Chemical profiling of Radix Paeoniae evaluated by ultra-performance liquid chromatography/photo-diode-array/quadrupole time-of-flight mass spectrometry. J. Pharm. Biomed. Anal. 2009;49(2):253-266.
Li W, Li Y, Jiang X, Li X, Yu Z. Compound ammonium glycyrrhizin protects hepatocytes from injury induced by lipopolysaccharide/florfenicol through a mitochondrial pathway. Molecules 2018;23(9):2378.
Li XH, Dai CF, Chen L, Zhou WT, Han HL, Dong ZF. 7,8-dihydroxyflavone ameliorates motor deficits via suppressing α-synuclein expression and oxidative stress in the MPTP-induced mouse model of Parkinson’s disease. CNS Neurosci. Ther. 2016;22(7):617-624.
Liao WY, Tsai TH, Ho TY, Lin YW, Cheng CY, Hsieh CL. Neuroprotective effect of paeonol mediates anti-inflammation via suppressing toll-like receptor 2 and toll-like receptor 4 signaling pathways in cerebral ischemia-reperfusion injured rats. Evid. Based Complement. Alternat. Med. 2016;2016:3704647.
Lin CH, Hsieh YS, Wu YR, Hsu CJ, Chen HC, Huang WH, Chang KH, Hsieh-Li HM, Su MT, Sun YC, et al. Identifying GSK-3β kinase inhibitors of Alzheimer’s disease: virtual screening, enzyme, and cell assays. Eur. J. Pharm. Sci. 2016;89:11-19.
Lin TH, Chiu YJ, Lin CH, Lin CY, Chao CY, Chen YC, Yang SM, Lin W, Hsieh-Li HM, Wu YR, et al. Exploration of multi-target effects of 3-benzoyl-5-hydroxychromen-2-one in Alzheimer’s disease cell and mouse models. Aging Cell 2020;19(7):e13169.
Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Deliv. Rev. 1997;23(1-3):3-25.
Lipton SA, Rezaie T, Nutter A, Lopez KM, Parker J, Kosaka K, Satoh T, McKercher SR, Masliah E, Nakanishi N. Therapeutic advantage of pro-electrophilic drugs to activate the Nrf2/ARE pathway in Alzheimer’s disease models. Cell Death Dis. 2016;7(12):e2499.
Lisman J, Yasuda R, Raghavachari S. Mechanisms of CaMKII action in long-term potentiation. Nat. Rev. Neurosci. 2012;13(3):169-182.
Liu C, Chan CB, Ye K. 7,8-dihydroxyflavone, a small molecular TrkB agonist, is useful for treating various BDNF-implicated human disorders. Transl. Neurodegener. 2016;5:2.
Liu F, Grundke-Iqbal I, Iqbal K, Gong CX. Contributions of protein phosphatases PP1, PP2A, PP2B and PP5 to the regulation of Tau phosphorylation. Eur. J. Neurosci. 2005;22(8):1942-1950.
Liu H, Jin X, Yin X, Jin N, Liu F, Qian W. PKA-CREB signaling suppresses Tau transcription. J. Alzheimers Dis. 2015;46(1):239-248.
Liu Q, Smith MA, Avilá J, DeBernardis J, Kansal M, Takeda A, Zhu X, Nunomura A, Honda K, Moreira PI, et al. Alzheimer-specific epitopes of Tau represent lipid peroxidation-induced conformations. Free Radic. Biol. Med. 2005;38(6):746-754.
Long JM, Holtzman DM. Alzheimer disease: An update on pathobiology and treatment strategies. Cell 2019;179(2):312-339.
Longo FM, Yang T, Knowles JK, Xie Y, Moore LA, Massa SM. Small molecule neurotrophin receptor ligands: novel strategies for targeting Alzheimer’s disease mechanisms. Curr. Alzheimer Res. 2007;4(5):503-506.
Lonze BE, Ginty DD. Function and regulation of CREB family transcription factors in the nervous system. Neuron 2002;35(4):605-623.
Lovestone S, Hartley CL, Pearce J, Anderton BH. Phosphorylation of Tau by glycogen synthase kinase-3β in intact mammalian cells: the effects on the organization and stability of microtubules. Neuroscience 1996;73(4):1145-1157.
Ma Q. Role of nrf2 in oxidative stress and toxicity. Annu. Rev. Pharmacol. Toxicol. 2013;53:401-426.
Maccioni RB, Rojo RE, Fernández JA, Kuljis RO. The role of neuroimmunomodulation in Alzheimer’s disease. Ann. NY Acad. Sci. 2009;1153:240-246.
Mahoney R, Thomas EO, Ramirez P, Miller HE, Beckmann A, ZunigaG, Dobrowolski R, Frost B. Pathogenic Tau causes a toxic depletion of nuclear calcium. Cell Rep. 2020;32(2):107900.
Mandelkow E, von Bergen M, Biernat J, Mandelkow EM. Structural principles of Tau and the paired helical filaments of Alzheimer’s disease. Brain Pathol. 2007;17(1):83-90.
Mandelkow EM, Mandelkow E. Microtubules and microtubule-associated proteins. Curr. Opin. Cell Biol. 1995;7(1):72-81.
Mann DMA, Snowden JS. Frontotemporal lobar degeneration: Pathogenesis, pathology and pathways to phenotype. Brain Pathol. 2017;27(6):723-736.
Maria Pia GD, Sara F, Mario F, Lorenza S. Biological effects of licochalcones. Mini Rev. Med. Chem. 2019;19(8):647-656.
Matsui S, Matsumoto H, Sonoda Y, Ando K, Aizu-Yokota E, Sato T, Kasahara T. Glycyrrhizin and related compounds down-regulate production of inflammatory chemokines IL-8 and eotaxin 1 in a human lung fibroblast cell line. Int. Immunopharmacol. 2004;4(13):1633-1644.
McGeer PL, Kawamata T, Walker DG, Akiyama H, Tooyama I, McGeer EG. Microglia in degenerative neurological disease. Glia 1993;7(1):84-92.
McKee AC, Carreras I, Hossain L, Ryu H, Klein WL, Oddo S, LaFerla FM, Jenkins BG, Kowall NW, Dedeoglu A. Ibuprofen reduces Aβ, hyperphosphorylated Tau and memory deficits in Alzheimer mice. Brain Res. 2008;1207:225-236.
Meier S, Bell M, Lyons DN, Rodriguez-Rivera J, Ingram A, Fontaine SN, Mechas E, Chen J, Wolozin B, LeVine 3rd H, et al. Pathological Tau promotes neuronal damage by impairing ribosomal function and decreasing protein synthesis. J. Neurosci. 2016;36(3):1001-1007.
Melo JB, Agostinho P, Oliveira CR. Involvement of oxidative stress in the enhancement of acetylcholinesterase activity induced by amyloid β-peptide. Neurosci. Res. 2003;45(1):117-127.
Melov S, Adlard PA, Morten K, Johnson F, Golden TR, Hinerfeld D, Schilling B, Mavros C, Masters CL, Volitakis I, et al. Mitochondrial oxidative stress causes hyperphosphorylation of Tau. PLoS One 2007;2(6):e536.
Minichiello L. TrkB signalling pathways in LTP and learning. Nat. Rev. Neurosci. 2009;10(12):850-860.
Mitre M, Mariga A, Chao MV. Neurotrophin signalling: novel insights into mechanisms and pathophysiology. Clin. Sci. (Lond). 2017;131(1):13-23.
Mohammadi A, Amooeian VG, Rashidi E. Dysfunction in brain-derived neurotrophic factor signaling pathway and susceptibility to schizophrenia, Parkinson’s and Alzheimer’s diseases. Curr. Gene Ther. 2018;18(1):45-63.
Monie TP, Bryant CE. Caspase-8 functions as a key mediator of inflammation and pro-IL-1β processing via both canonical and non-canonical pathways. Immunol. Rev. 2015;265(1):181-193.
Morishima-Kawashima M, Hasegawa M, Takio K, Suzuki M, Yoshida H, Titani K, Ihara Y. Proline-directed and non-proline-directed phosphorylation of PHF-Tau. J. Biol. Chem. 1995;270(2):823-829.
Morley JE, Farr SA, Nguyen AD, Xu F. Editorial: What is the physiological function of amyloid-β protein? J. Nutr. Health Aging. 2019;23(3):225-226.
Morsch R, Simon W, Coleman PD. Neurons may live for decades with neurofibrillary tangles. J. Neuropathol. Exp. Neurol. 1999;58(2):188-197.
Mukrasch MD, Bibow S, Korukottu J, Jeganathan S, Biernat J, Griesinger C, Mandelkow E, Zweckstetter M. Structural polymorphism of 441-residue Tau at single residue resolution. PLoS Biol. 2009;7(2):e34.
Mullan M, Crawford F, Axelman K, Houlden H, Lilius L, Winblad B, Lannfelt L. A pathogenic mutation for probable Alzheimer’s disease in the APP gene at the N-terminus of β-amyloid. Nat. Genet. 1992;1(5):345-347.
Naini SMA, Soussi-Yanicostas N. Tau hyperphosphorylation and oxidative stress, a critical vicious circle in neurodegenerative tauopathies? Oxid. Med. Cell. Longev. 2015;2015:151979.
Neve RL, Harris P, Kosik KS, Kurnit DM, Donlon TA. Identification of cDNA clones for the human microtubule-associated protein Tau and chromosomal localization of the genes for Tau and microtubule-associated protein 2. Brain Res. 1986;387(3):271-280.
Nissink JWM, Murray C, Hartshorn M, Verdonk ML, Cole JC, Taylor R. A new test set for validating predictions of protein-ligand interaction. Proteins 2002;49(4):457-471.
Noble W, Olm V, Takata K, Casey E, Mary O, Meyerson J, Gaynor K, LaFrancois J, Wang L, Kondo T, et al. Cdk5 is a key factor in Tau aggregation and tangle formation in vivo. Neuron 2003;38(4):555-565.
Noël A, Foveau B, LeBlanc AC. Caspase-6-cleaved Tau fails to induce Tau hyperphosphorylation and aggregation, neurodegeneration, glial inflammation, and cognitive deficits. Cell Death Dis. 2021;12(3):227.
Noufi P, Khoury R, Jeyakumar S, Grossberg GT. Use of cholinesterase inhibitors in non-Alzheimer’s dementias. Drugs Aging 2019;36(8):719-731.
Numakawa T, Suzuki S, Kumamaru E, Adachi N, Richards M, Kunugi H. BDNF function and intracellular signaling in neurons. Histol. Histopathol. 2010;25(2):237-258.
Nunomura A, Perry G, Aliev G, Hirai K, Takeda A, Balraj EK, Jones PK, Ghanbari H, Wataya T, Shimohama S, et al. Oxidative damage is the earliest event in Alzheimer disease. J. Neuropathol. Exp. Neurol. 2001;60(8):759-767.
O’Brien RJ, Wong PC. Amyloid precursor protein processing and Alzheimer’s disease. Annu. Rev. Neurosci. 2011;34:185-204.
Obulesu M, Lakshmi MJ. Apoptosis in Alzheimer’s disease: an understanding of the physiology, pathology and therapeutic avenues. Neurochem. Res. 2014;39(12):2301-2312.
Ottaviani G, Martel S, Escarala C, Nicolle E, Carrupt PA. The PAMPA technique as a HTS tool for partition coefficients determination in different solvent/water systems. Eur. J. Pharm. Sci. 2008;35(1-2):68-75.
Påhlman S, Ruusala AI, Abrahamsson L, Mattsson ME, Esscher T. Retinoic acid-induced differentiation of cultured human neuroblastoma cells: a comparison with phorbolester-induced differentiation. Cell Differ. 1984;14(2):135-144.
Pajares M, Jiménez-Moreno N, García-Yagüe AJ, Escoll M, de Ceballos ML, Van Leuven F, Rábano A, Yamamoto M, Rojo AI, Cuadrado A. Transcription factor NFE2L2/NRF2 is a regulator of macroautophagy genes. Autophagy 2016;12(10):1902-1916.
Pankiewicz P, Szybiński M, Kisielewska K, Gołębiowski F, Krzemiński P, Rutkowska-Włodarczyk I, Moszczyński-Pętkowski R, Gurba-Bryśkiewicz L, Delis M, Mulewski K, et al. Do small molecules activate the TrkB receptor in the same manner as BDNF? Limitations of published TrkB low molecular agonists and screening for novel TrkB orthosteric agonists. Pharmaceuticals (Basel) 2021;14(8):704.
Park H, Poo M. Neurotrophin regulation of neural circuit development and function. Nat. Rev. Neurosci. 2013;14(1):7-23.
Parker S, May B, Zhang C, Zhang AL, Lu C, Xue CC. A Pharmacological review of bioactive constituents of Paeonia lactiflora Pallas and Paeonia veitchii Lynch. Phytother. Res. 2016;30(9):1445-1473.
Pei H, Ma L, Cao Y, Wang F, Li Z, Liu N, Liu M, Wei Y, Li H. Traditional Chinese medicine for Alzheimer’s disease and other cognitive impairment: A review. Am. J. Chin. Med. 2020;48(3):487-511.
Pei JJ, Braak E, Braak H, Grundke-Iqbal I, Iqbal K, Winblad B, Cowburn RF. Localization of active forms of C-jun kinase (JNK) and p38 kinase in Alzheimer’s disease brains at different stages of neurofibrillary degeneration. J. Alzheimers Dis. 2001;3(1):41-48.
Pei JJ, Braak H, An WL, Winblad B, Cowburn RF, Iqbal K, Grundke-Iqbal I. Up-regulation of mitogen-activated protein kinases ERK1/2 and MEK1/2 is associated with the progression of neurofibrillary degeneration in Alzheimer’s disease. Brain Res. Mol. Brain Res. 2002;109(1-2):45-55.
Perry G, Roder H, Nunomura A, Takeda A, Friedlich AL, Zhu X, Raina AK, Holbrook N, Siedlak SL, Harris PL, et al. Activation of neuronal extracellular receptor kinase (ERK) in Alzheimer disease links oxidative stress to abnormal phosphorylation. Neuroreport 1999;10(11):2411-2415.
Perry G, Nunomura A, Hirai K, Zhu X, Pérez M, Avila J, Castellani RJ, Atwood CS, Aliev G, Sayre LM, et al. Is oxidative damage the fundamental pathogenic mechanism of Alzheimer’s and other neurodegenerative diseases? Free Radic. Biol. Med. 2002a;33(11):1475-1479.
Perry G, Cash AD, Smith MA. Alzheimer disease and oxidative stress. J. Biomed. Biotechnol. 2002b;2(3):120-123.
Persson T, Popescu BO, Cedazo-Minguez A. Oxidative stress in Alzheimer’s disease: why did antioxidant therapy fail? Oxid. Med. Cell. Longev. 2014;2014:427318.
Preuss U, Biernat J, Mandelkow EM, Mandelkow E. The ‘jaws’ model of Tau-microtubule interaction examined in CHO cells. J. Cell Sci. 1997;110(Pt 6):789-800.
Pugazhenthi S, Wang M, Pham S, Sze CI, Eckman CB. Downregulation of CREB expression in Alzheimer’s brain and in Aβ-treated rat hippocampal neurons. Mol. Neurodegener. 2011;6:60.
Qi H, Prabakaran S, Cantrelle FX, Chambraud B, Gunawardena J, Lippens G, Landrieu I. Characterization of neuronal Tau protein as a target of extracellular signal-regulated kinase. J. Biol. Chem. 2016;291(14):7742-7753.
Qian W, Liang H, Shi J, Jin N, Grundke-Iqbal I, Iqbal K, Gong CX, Liu F. Regulation of the alternative splicing of Tau exon 10 by SC35 and Dyrk1A. Nucleic Acids Res. 2011;39(14):6161-6171.
Qin HL, Zhang ZW, Lekkala R, Alsulami H, Rakesh KP. Chalcone hybrids as privileged scaffolds in antimalarial drug discovery: A key review. Eur. J. Med. Chem. 2020;193:112215.
Ramsey CP, Glass CA, Montgomery MB, Lindl KA, Ritson GP, Chia LA, Hamilton RL, Chu CT, Jordan-Sciutto KL. Expression of Nrf2 in neurodegenerative diseases. J. Neuropathol. Exp. Neurol. 2007;66(1):75-85.
Reese LC, Laezza F, Woltjer R, Taglialatela G. Dysregulated phosphorylation of Ca2+/calmodulin-dependent protein kinase II-α in the hippocampus of subjects with mild cognitive impairment and Alzheimer’s disease. J. Neurochem. 2011;119(4):791-804.
Rissman RA, Poon WW, Blurton-Jones M, Oddo S, Torp R, Vitek MP, LaFerla FM, Rohn TT, Cotman CW. Caspase-cleavage of Tau is an early event in Alzheimer disease tangle pathology. J. Clin. Invest. 2004;114(1):121-130.
Rizzu P, Van Swieten JC, Joosse M, Hasegawa M, Stevens M, Tibben A, Niermeijer MF, Hillebrand M, Ravid R, Oostra BA, et al. High prevalence of mutations in the microtubule-associated protein Tau in a population study of frontotemporal dementia in the Netherlands. Am. J. Hum. Genet. 1999;64(2):414-421.
Rodríguez-Gómez JA, Kavanagh E, Engskog-Vlachos P, Engskog MKR, Herrera AJ, Espinosa-Oliva AM, Joseph B, Hajji N, Venero JL, Burguillos MA. Microglia: Agents of the CNS pro-inflammatory response. Cells 2020;9(7):1717.
Rohn TT, Head E, Su JH, Anderson AJ, Bahr BA, Cotman CW, Cribbs DH. Correlation between caspase activation and neurofibrillary tangle formation in Alzheimer’s disease. Am. J. Pathol. 2001;158(1):189-198.
Rosa E, Mahendram S, Ke YD, Ittner LM, Ginsberg SD, Fahnestock M. Tau downregulates BDNF expression in animal and cellular models of Alzheimer’s disease. Neurobiol. Aging 2016;48:135-142.
Sahara N, Maeda S, Yoshiike Y, Mizoroki T, Yamashita S, Murayama M, Park JM, Saito Y, Murayama S, Takashima A. Molecular chaperone-mediated Tau protein metabolism counteracts the formation of granular Tau oligomers in human brain. J. Neurosci. Res. 2007;85(14):3098-3108.
Sánchez S, Jiménez C, Carrera AC, Diaz-Nido J, Avila J, Wandosell F. A cAMP-activated pathway, including PKA and PI3K, regulates neuronal differentiation. Neurochem. Int. 2004;44(4):231-242.
Sánchez-Juan P, Moreno S, de Rojas I, Hernández I, Valero S, Alegret M, Montrreal L, García González P, Lage C, López-García S, et al. The MAPT H1 haplotype is a risk factor for Alzheimer’s disease in APOE ε4 non-carriers. Front. Aging Neurosci. 2019;11:327.
Sannerud R, Esselens C, Ejsmont P, Mattera R, Rochin L, Tharkeshwar AK, De Baets G, De Wever V, Habets R, Baert V, et al. Restricted location of PSEN2/γ-secretase determines substrate specificity and generates an intracellular Aβ pool. Cell 2016;166(1):193-208.
Santacruz K, Lewis J, Spires T, Paulson J, Kotilinek L, Ingelsson M, Guimaraes A, DeTure M, Ramsden M, McGowan E, et al. Tau suppression in a neurodegenerative mouse model improves memory function. Science 2005;309(5733):476-481.
Saresella M, La Rosa F, Piancone F, Zoppis M, Marventano I, Calabrese E, Rainone V, Nemni R, Mancuso R, Clerici M. The NLRP3 and NLRP1 inflammasomes are activated in Alzheimer’s disease. Mol. Neurodegener. 2016;11:23.
Sasaki A, Kawarabayashi T, Murakami T, Matsubara E, Ikeda M, Hagiwara H, Westaway D, George-Hyslop PS, Shoji M, Nakazato Y. Microglial activation in brain lesions with Tau deposits: comparison of human tauopathies and Tau transgenic mice TgTauP301L. Brain Res. 2008;1214:159-168.
Saunders AM, Strittmatter WJ, Schmechel D, George-Hyslop PH, Pericak-Vance MA, Joo SH, Rosi BL, Gusella JF, Crapper-MacLachlan DR, Alberts MJ, et al. Association of apolipoprotein E allele epsilon 4 with late-onset familial and sporadic Alzheimer’s disease. Neurology 1993;43(8):1467-1472.
Saura CA, Valero J. The role of CREB signaling in Alzheimer’s disease and other cognitive disorders. Rev. Neurosci. 2011;22(2):153-169.
Sedger LM, McDermott MF. TNF and TNF-receptors: From mediators of cell death and inflammation to therapeutic giants - past, present and future. Cytokine Growth Factor Rev. 2014;25(4):453-472.
Seidler EM, Boyer DR, Rodriguez JA, Sawaya MR, Cascio D, Murray K, Gonen T, Eisenberg DS. Structure-based inhibitors of Tau aggregation. Nat. Chem. 2018;10(2):170-176.
Seki N, Takahashi H, Yamamoto K, Ogawa K, Onji T, Adachi N, Tanaka S, Hide I, Saito N, Sakai N. Congo red, an amyloid-inhibiting compound, alleviates various types of cellular dysfunction triggered by mutant protein kinase cγ that causes spinocerebellar ataxia type 14 (SCA14) by inhibiting oligomerization and aggregation. J. Pharmacol. Sci. 2010;114(2):206-216.
Serenó L, Coma M, Rodríguez M, Sánchez-Ferrer P, Sánchez MB, Gich I, Agulló JM, Pérez M, Avila J, Guardia-Laguarta C, et al. A novel GSK-3β inhibitor reduces Alzheimer’s pathology and rescues neuronal loss in vivo. Neurobiol. Dis. 2009;35(3):359-367.
Serrano-Pozo A, Frosch MP, Masliah E, Hyman BT. Neuropathological alterations in Alzheimer disease. Cold Spring Harb. Perspect. Med. 2011;1(1):a006189.
Shi Y, Yamada K, Liddelow SA, Smith ST, Zhao L, Luo W, Tsai RM, Spina S, Grinberg LT, Rojas JC, et al. ApoE4 markedly exacerbates Tau-mediated neurodegeneration in a mouse model of tauopathy. Nature 2017;549(7673):523-527.
Shimura H, Miura-Shimura Y, Kosik KS. Binding of Tau to heat shock protein 27 leads to decreased concentration of hyperphosphorylated Tau and enhanced cell survival. J. Biol. Chem. 2004;279(17):17957-17962.
Silveyra MX, García-Ayllón MS, de Barreda EG, Small DH, Martínez S, Avila J, Sáez-Valero J. Altered expression of brain acetylcholinesterase in FTDP-17 human Tau transgenic mice. Neurobiol. Aging. 2012;33(3):624.e23-34.
Šimić G, Leko MB, Wray S, Harrington C, Delalle I, Jovanov-Milošević N, Bažadona D, Buée L, de Silva R, Di Giovanni G, et al. Tau protein hyperphosphorylation and aggregation in Alzheimer’s disease and other tauopathies, and possible neuroprotective strategies. Biomolecules 2016;6(1):6.
Singh TJ, Zaidi T, Grundke-Iqbal I, Iqbal K. Non-proline-dependent protein kinases phosphorylate several sites found in Tau from Alzheimer disease brain. Mol. Cell. Biochem. 1996;154(2):143-151.
Smith JA, Das S, Ray SK, Banik NL. Role of pro-inflammatory cytokines released from microglia in neurodegenerative diseases. Brain Res. Bull. 2012;87(1):10-20.
Sperber BR, Leight S, Goedert M, Lee VM. Glycogen synthase kinase-3β phosphorylates Tau protein at multiple sites in intact cells. Neurosci. Lett. 1995;197(2):149-153.
Spillantini MG, Murrell JR, Goedert M, Farlow MR, Klug A, Ghetti B. Mutation in the Tau gene in familial multiple system tauopathy with presenile dementia. Proc. Natl. Acad. Sci. U. S. A. 1998;95(13):7737-7741.
Stamer K, Vogel R, Thies E, Mandelkow E, Mandelkow EM. Tau blocks traffic of organelles, neurofilaments, and APP vesicles in neurons and enhances oxidative stress. J. Cell Biol. 2002;156(6):1051-1063.
Stancu IC, Cremers N, Vanrusselt H, Couturier J, Vanoosthuyse A, Kessels S, Lodder C, Brône B, Huaux F, Octave JN, et al. Aggregated Tau activates NLRP3-ASC inflammasome exacerbating exogenously seeded and non-exogenously seeded Tau pathology in vivo. Acta Neuropathol. 2019;137(4):599-617.
Strang KH, Golde TE, Giasson BI. MAPT mutations, tauopathy, and mechanisms of neurodegeneration. Lab. Invest. 2019;99(7):912-928.
Strassnig M, Ganguli M. About a peculiar disease of the cerebral cortex: Alzheimer’s original case revisited. Psychiatry (Edgmont) 2005;2(9):30-33.
Stratman NC, Castle CK, Taylor BM, Epps DE, Melchior GW, Carter DB. Isoform-specific interactions of human apolipoprotein E to an intermediate conformation of human Alzheimer amyloid-β peptide. Chem. Phys. Lipids 2005;137(1-2):52-61.
Sun P, Enslen H, Myung PS, Maurer RA. Differential activation of CREB by Ca2+/calmodulin-dependent protein kinases type II and type IV involves phosphorylation of a site that negatively regulates activity. Genes Dev. 1994;8(21):2527-2539.
Sun ZK, Yang HQ, Chen SD. Traditional Chinese medicine: a promising candidate for the treatment of Alzheimer’s disease. Transl. Neurodegener. 2013;2(1):6.
Sundaram JR, Poore CP, Sulaimee NHB, Pareek T, Asad ABMA, Rajkumar R, Cheong WF, Wenk MR, Dawe GS, Chuang KH, et al. Specific inhibition of p25/Cdk5 activity by the Cdk5 inhibitory peptide reduces neurodegeneration in vivo. J. Neurosci. 2013;33(1):334-343.
Talesa VN. Acetylcholinesterase in Alzheimer’s disease. Mech. Ageing Dev. 2001;122(16):1961-1699.
Tan Y, Rouse J, Zhang A, Cariati S, Cohen P, Comb MJ. FGF and stress regulate CREB and ATF-1 via a pathway involving p38 MAP kinase and MAPKAP kinase-2. EMBO J. 1996;15(17):4629-4642.
Tapia-Arancibia L, Aliaga E, Silhol M, Arancibia S. New insights into brain BDNF function in normal aging and Alzheimer disease. Brain Res. Rev. 2008;59(1):201-220.
Tarutani A, Hasegawa M. Prion-like propagation of α-synuclein in neurodegenerative diseases. Prog. Mol. Biol. Transl. Sci. 2019;168:323-348.
Tenreiro S, Eckermann K, Outeiro TF. Protein phosphorylation in neurodegeneration: friend or foe? Front. Mol. Neurosci. 2014;7:42.
Tönnies E, Trushina E. Oxidative stress, synaptic dysfunction, and Alzheimer’s disease. J. Alzheimers Dis. 2017;57(4):1105-1121.
Tóth ME, Szegedi V, Varga E, Juhász G, Horváth J, Borbély E, Csibrány B, Alföldi R, Lénárt N, Penke B, et al. Overexpression of Hsp27 ameliorates symptoms of Alzheimer’s disease in APP/PS1 mice. Cell Stress Chaperones 2013;18(6):759-771.
Trinczek B, Biernat J, Baumann K, Mandelkow EM, Mandelkow E. Domains of Tau protein, differential phosphorylation, and dynamic instability of microtubules. Mol. Biol. Cell. 1995;6(12):1887-1902.
Trinczek B, Ebneth A, Mandelkow EM, Mandelkow E. Tau regulates the attachment/detachment but not the speed of motors in microtubule-dependent transport of single vesicles and organelles. J. Cell Sci. 1999;112 (14):2355-2367.
Urfer R, Tsoulfas P, O’Connell L, Shelton DL, Parada LF, Presta LG. An immunoglobulin-like domain determines the specificity of neurotrophin receptors. EMBO J. 1995;14(12):2795-2805.
Vassar PS, Culling CFA. Fluorescent stains with special reference to amyloid and connective tissues. Arch. Pathol. 1959;68:487-498.
Vendredy L, Adriaenssens E, Timmerman V. Small heat shock proteins in neurodegenerative diseases. Cell Stress Chaperones 2020;25(4):679-699.
Verdonk ML, Cole JC, Hartshorn MJ, Murray CW, Taylor RD. Improved protein-ligand docking using GOLD. Proteins 2003;52(4):609-623.
Vitolo OV, Sant’Angelo A, Costanzo V, Battaglia F, Arancio O, Shelanski M. Amyloid β-peptide inhibition of the PKA/CREB pathway and long-term potentiation: reversibility by drugs that enhance cAMP signaling. Proc. Natl. Acad. Sci. U S A. 2002;99(20):13217-13221.
von Bergen M, Barghorn S, Li L, Marx A, Biernat J, Mandelkow EM, Mandelkow E. Mutations of Tau protein in frontotemporal dementia promote aggregation of paired helical filaments by enhancing local β-structure. J. Biol. Chem. 2001;276(51):48165-48174.
Walker LC, Schelle J, Jucker M. The prion-like properties of amyloid-β assemblies: Implications for Alzheimer’s disease. Cold Spring Harb. Perspect. Med. 2016;6(7):a024398.
Walter S, Letiembre M, Liu Y, Heine H, Penke B, Hao W, Bode B, Manietta N, Walter J, Schulz-Schuffer W, et al. Role of the toll-like receptor 4 in neuroinflammation in Alzheimer’s disease. Cell. Physiol. Biochem. 2007;20(6):947-956.
Walton M, Woodgate AM, Muravlev A, Xu R, During MJ, Dragunow M. CREB phosphorylation promotes nerve cell survival. J. Neurochem. 1999;73(5):1836-1842.
Wang B, Wu N, Liang F, Zhang S, Ni W, Cao Y, Xia D, Xi H. 7,8-dihydroxyflavone, a small-molecule tropomyosin-related kinase B (TrkB) agonist, attenuates cerebral ischemia and reperfusion injury in rats. J. Mol. Histol. 2014;45(2):129-140.
Wang D, Liang J, Zhang J, Wang Y, Chai X. Natural chalcones in Chinese materia medica: Licorice. Evid. Based Complement. Alternat. Med. 2020;2020:3821248.
Wang JM, Yang LH, Zhang YY, Niu CL, Cui Y, Feng WS, Wang GF. BDNF and COX-2 participate in anti-depressive mechanisms of catalpol in rats undergoing chronic unpredictable mild stress. Physiol. Behav. 2015;151:360-368.
Wang JZ, Xia YY, Grundke-Iqbal I, Iqbal K. Abnormal hyperphosphorylation of Tau: sites, regulation, and molecular mechanism of neurofibrillary degeneration. J. Alzheimers Dis. 2013;33 Suppl 1:S123-S139.
Wang X, Wang Z, Yao Y, Li J, Zhang X, Li C, Cheng Y, Ding G, Liu L, Ding Z. Essential role of ERK activation in neurite outgrowth induced by α-lipoic acid. Biochim. Biophys. Acta. 2011;1813(5):827-838.
Wang X, Becker K, Levine N, Zhang M, Lieberman AP, Moore DJ, Ma J. Pathogenic α-synuclein aggregates preferentially bind to mitochondria and affect cellular respiration. Acta. Neuropathol. Commun. 2019;7(1):41.
Wang Y, Mandelkow E. Tau in physiology and pathology. Nat. Rev. Neurosci. 2016;17(1):5-21.
Wang YJ, Chen GH, Hu XY, Lu YP, Zhou JN, Liu RY. The expression of calcium/calmodulin-dependent protein kinase II-alpha in the hippocampus of patients with Alzheimer’s disease and its links with AD-related pathology. Brain Res. 2005;1031(1):101-108.
Weingarten MD, Lockwood AH, Hwo SY, Kirschner MW. A protein factor essential for microtubule assembly. Proc. Natl. Acad. Sci. U. S. A. 1975;72(5):1858-1862.
Williamson R, Scales T, Clark BR, Gibb G, Reynolds CH, Kellie S, Bird IN, Varndell IM, Sheppard PW, Everall I, et al. Rapid tyrosine phosphorylation of neuronal proteins including Tau and focal adhesion kinase in response to amyloid-β peptide exposure: involvement of Src family protein kinases. J. Neurosci. 2002;22(1):10-20.
Woods YL, Cohen P, Becker W, Jakes R, Goedert M, Wang X, Proud CG. The kinase DYRK phosphorylates protein-synthesis initiation factor eIF2Bepsilon at Ser539 and the microtubule-associated protein Tau at Thr212: potential role for DYRK as a glycogen synthase kinase 3-priming kinase. Biochem. J. 2001;355(Pt 3):609-615.
Xin Q, Yuan R, Shi W, Zhu Z, Wang Y, Cong W. A review for the anti-inflammatory effects of paeoniflorin in inflammatory disorders. Life Sci. 2019;237:116925.
Yang R, Yuan BC, Ma YS, Zhou S, Liu Y. The anti-inflammatory activity of licorice, a widely used Chinese herb. Pharm. Biol. 2017b;55(1):5-18.
Yang WT, Zheng XW, Chen S, Shan CS, Xu QQ, Zhu JZ, Bao XY, Lin Y, Zheng GQ, Wang Y. Chinese herbal medicine for Alzheimer’s disease: Clinical evidence and possible mechanism of neurogenesis. Biochem. Pharmacol. 2017a;141:143-155.
Ye X, Tai W, Zhang D. The early events of Alzheimer’s disease pathology: from mitochondrial dysfunction to BDNF axonal transport deficits. Neurobiol. Aging 2012;33(6):1122.e1-1122.e10.
Yin Y, Gao D, Wang Y, Wang ZH, Wang X, Ye J, Wu D, Fang L, Pi G, Yang Y, et al. Tau accumulation induces synaptic impairment and memory deficit by calcineurin-mediated inactivation of nuclear CaMKIV/CREB signaling. Proc. Natl. Acad. Sci. U. S. A. 2016;113(26):E3773-E3781.
Yoshida H, Hastie CJ, McLauchlan H, Cohen P, Goedert M. Phosphorylation of microtubule-associated protein Tau by isoforms of c-Jun N-terminal kinase (JNK). Neurochem. 2004;90(2):352-358.
Yoshida M. Astrocytic inclusions in progressive supranuclear palsy and corticobasal degeneration. Neuropathology 2014;34(6):555-570.
Yoshiyama Y, Higuchi M, Zhang B, Huang SM, Iwata N, Saido TC, Maeda J, Suhara T, Trojanowski JQ, Lee VMY. Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron 2007;53(3):337-351.
Zhang CC, Xing A, Tan MS, Tan L, Yu JT. The Role of MAPT in neurodegenerative diseases: genetics, mechanisms and therapy. Mol. Neurobiol. 2016;53(7):4893-4904.
Zhang HR, Peng JH, Cheng XB, Shi BZ, Zhang MY, Xu RX. Paeoniflorin atttenuates amyloidogenesis and the inflammatory responses in a transgenic mouse model of Alzheimer’s disease. Neurochem. Res. 2015;40(8):1583-1592.
Zhang Q, Ye M. Chemical analysis of the Chinese herbal medicine Gan-Cao (licorice). J. Chromatogr. A 2009;1216(11):1954-1969.
Zhang X, Li F, Bulloj A, Zhang YW, Tong G, Zhang Z, Liao FF, Xu H. Tumor-suppressor PTEN affects Tau phosphorylation, aggregation, and binding to microtubules. FASEB J. 2006;20(8):1272-1274.
Zhang Z, Liu X, Schroeder JP, Chan CB, Song M, Yu SP, Weinshenker D, Ye K. 7,8-dihydroxyflavone prevents synaptic loss and memory deficits in a mouse model of Alzheimer’s disease. Neuropsychopharmacology 2014;39(3):638-650.
Zhao H, Wang SL, Qian L, Jin JL, Li H, Xu Y, Zhu XL. Diammonium glycyrrhizinate attenuates Aβ1-42-induced neuroinflammation and regulates MAPK and NF-κB pathways in vitro and in vivo. CNS Neurosci. Ther. 2013;19(2):117-124.
Zhou F, Wang D. The associations between the MAPT polymorphisms and Alzheimer’s disease risk: a meta-analysis. Oncotarget 2017;8(26):43506-43520.
Zhou J, Wang L, Wang J, Wang C, Yang Z, Wang C, Zhu Y, Zhang J. Paeoniflorin and albiflorin attenuate neuropathic pain via MAPK pathway in chronic constriction injury rats. Evid. Based Complement. Alternat. Med. 2016;2016:8082753.
Zhou YX, Gong XH, Zhang H, Peng C. A review on the pharmacokinetics of paeoniflorin and its anti-inflammatory and immunomodulatory effects. Biomed. Pharmacother. 2020;130:110505.
Zhu JJ, Jiang JG. Pharmacological and nutritional effects of natural coumarins and their structure-activity relationships. Mol. Nutr. Food Res. 2018;e1701073.
Zhuang C, Zhang W, Sheng C, Zhang W, Xing C, Miao Z. Chalcone: A privileged structure in medicinal chemistry. Chem. Rev. 2017;117(12):7762-7810.
Zuk M, Kulma A, Dymińska L, Szołtysek K, Prescha A, Hanuza J, Szopa J. Flavonoid engineering of flax potentiate its biotechnological application. BMC Biotechnol. 2011;11:10.