Natural Products Targeting Tau Protein Phosphorylation: A Promising Therapeutic Avenue for Alzheimerʼs Disease

Ziying Chen; Yan Lu; Yiyun Wang; Qi Wang; Liangwen Yu; Jinman Liu

doi:10.1055/a-2536-8919

Planta Medica, Inhaltsverzeichnis

Planta Med
DOI: 10.1055/a-2536-8919

Reviews

Natural Products Targeting Tau Protein Phosphorylation: A Promising Therapeutic Avenue for Alzheimerʼs Disease

Ziying Chen

¹Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China

,

Yan Lu

¹Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China

,

Yiyun Wang

¹Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China

,

Qi Wang

¹Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China

,

Liangwen Yu

¹Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China

,

Jinman Liu

²Affiliated Jiangmen TCM Hospital of Jiʼnan University, Jiangmen, China

› Institutsangaben

Abstract

Alzheimerʼs disease is a progressive neurodegenerative disorder characterized by tau protein hyperphosphorylation and neurofibrillary tangle formation, which are central to its pathogenesis. This review focuses on the therapeutic potential of natural products in targeting tau phosphorylation, a key factor in Alzheimerʼs disease progression. It comprehensively summarizes current research on various natural compounds, including flavonoids, alkaloids, saponins, polysaccharides, phenols, phenylpropanoids, and terpenoids, highlighting their multitarget mechanisms, such as modulating kinases and phosphatases. The ability of these compounds to mitigate oxidative stress, inflammation, and tau pathology while enhancing cognitive function underscores their value as potential anti-Alzheimerʼs disease therapeutics. By integrating recent advances in extraction methods, pharmacological studies, and artificial intelligence-driven screening technologies, this review provides a valuable reference for future research and development of natural product-based interventions for Alzheimerʼs disease.

Keywords

Alzheimerʼs disease - tau phosphorylation - natural products - glycogen synthase kinase 3β (GSK-3β) - protein phosphatase 2A (PP2A) - neuroprotection

Volltext

Referenzen

References
1 Scheltens P, De Strooper B, Kivipelto M, Holstege H, Chételat G, Teunissen CE, Cummings J, van der Flier WM. Alzheimerʼs disease. Lancet 2021; 397: 1577-1590
2 Khan S, Barve KH, Kumar MS. Recent advancements in pathogenesis, diagnostics and treatment of Alzheimerʼs disease. Curr Neuropharmacol 2020; 18: 1106-1125
3 Hampel H, Hu Y, Hardy J, Blennow K, Chen C, Perry G, Kim SH, Villemagne VL, Aisen P, Vendruscolo M, Iwatsubo T, Masters CL, Cho M, Lannfelt L, Cummings JL, Vergallo A. The amyloid-β pathway in Alzheimerʼs disease: A plain language summary. Neurodegener Dis Manag 2023; 13: 141-149
4 Gueorguieva I, Willis BA, Chua L, Chow K, Ernest CS, Shcherbinin S, Ardayfio P, Mullins GR, Sims JR. Donanemab population pharmacokinetics, amyloid plaque reduction, and safety in participants with Alzheimerʼs disease. Clin Pharmacol Ther 2023; 113: 1258-1267
5 Munj SM, Patil PB. Drug discovery to drug development of BACE1 inhibitor as AntiAlzheimerʼs: A review. Curr Top Med Chem 2023; 23: 77-97
6 Ivanoiu A, Pariente J, Booth K, Lobello K, Luscan G, Hua L, Lucas P, Styren S, Yang L, Li D, Black RS, Brashear HR, McRae T. Long-term safety and tolerability of bapineuzumab in patients with AD in two phase 3 extension studies. Alzheimers Res Ther 2016; 8: 24
7 Henley DB, Sundell KL, Sethuraman G, Dowsett SA, May PC. Safety profile of semagacestat, a gamma-secretase inhibitor: IDENTITY trial findings. Curr Med Res Opin 2014; 30: 2021-2032
8 Egan MF, Mukai Y, Voss T, Kost J, Stone J, Furtek C, Mahoney E, Cummings JL, Tariot PN, Aisen PS, Vellas B, Lines C, Michelson D. Further analyses of the safety of verubecestat in the phase 3 EPOCH trial of mild-to-moderate Alzheimerʼs disease. Alzheimers Res Ther 2019; 11: 68
9 Gilman S, Koller M, Black RS, Jenkins L, Griffith SG, Fox NC, Eisner L, Kirby L, Rovira MB, Forette F, Orgogozo JM. AN1792(QS-21)-201 Study Team. Clinical effects of Abeta immunization (AN1792) in patients with AD in an interrupted trial. Neurology 2005; 64: 1553-1562
10 Vaz M, Silvestre S. Alzheimerʼs disease: Recent treatment strategies. Eur J Pharmacol 2020; 887: 173554
11 Chu D, Liu F. Pathological changes of tau related to Alzheimerʼs disease. ACS Chem Neurosci 2019; 10: 931-944
12 Saroja SR, Sharma A, Hof PR, Pereira AC. Differential expression of tau species and the association with cognitive decline and synaptic loss in Alzheimerʼs disease. Alzheimers Dement 2022; 18: 1602-1615
13 Niewiadomska G, Niewiadomski W, Steczkowska M, Gasiorowska A. Tau oligomers neurotoxicity. Life (Basel) 2021; 11: 28
14 Giovannini J, Smeralda W, Jouanne M, Sopkova-de Oliveira Santos J, Catto M, Voisin-Chiret AS. Tau protein aggregation: Key features to improve drug discovery screening. Drug Discov Today 2022; 27: 1284-1297
15 Yan H, Feng L, Li M. The role of traditional Chinese medicine natural products in β-amyloid deposition and tau protein hyperphosphorylation in Alzheimerʼs disease. Drug Des Devel Ther 2023; 17: 3295-3323
16 Lebouvier T, Scales TM, Williamson R, Noble W, Duyckaerts C, Hanger DP, Reynolds CH, Anderton BH, Derkinderen P. The microtubule-associated protein tau is also phosphorylated on tyrosine. J Alzheimers Dis 2009; 18: 1-9
17 Kitagishi Y, Nakanishi A, Ogura Y, Matsuda S. Dietary regulation of PI3K/AKT/GSK-3beta pathway in Alzheimerʼs disease. Alzheimer Res Ther 2014; 6: 35
18 Long HZ, Cheng Y, Zhou ZW, Luo HY, Wen DD, Gao LC. PI3K/AKT signal pathway: A target of natural products in the prevention and treatment of Alzheimerʼs disease and Parkinsonʼs disease. Front Pharmacol 2021; 12: 648636
19 Shukla V, Skuntz S, Pant HC. Deregulated Cdk5 activity is involved in inducing Alzheimerʼs disease. Arch Med Res 2012; 43: 655-662
20 Quintanilla RA, Orellana DI, Gonzalez-Billault C, Maccioni RB. Interleukin-6 induces Alzheimer-type phosphorylation of tau protein by deregulating the cdk5/p 35 pathway. Exp Cell Res 2004; 295: 245-257
21 Schwalbe M, Biernat J, Bibow S, Ozenne V, Jensen MR, Kadavath H, Blackledge M, Mandelkow E, Zweckstetter M. Phosphorylation of human tau protein by microtubule affinity-regulating kinase 2. Biochemistry 2013; 52: 9068-9079
22 Falcicchia C, Tozzi F, Arancio O, Watterson DM, Origlia N. Involvement of p 38 MAPK in synaptic function and dysfunction. Int J Mol Sci 2020; 21: 5624
23 Benítez MJ, Cuadros R, Jiménez JS. Phosphorylation and dephosphorylation of tau protein by the catalytic subunit of PKA, as probed by electrophoretic mobility retard. J Alzheimers Dis 2021; 79: 1143-1156
24 Sajan MP, Hansen BC, Higgs MG, Kahn CR, Braun U, Leitges M, Park CR, Diamond DM, Farese RV. Atypical PKC, PKCλ/ι, activates β-secretase and increases Aβ1–40/42 and phospho-tau in mouse brain and isolated neuronal cells, and may link hyperinsulinemia and other aPKC activators to development of pathological and memory abnormalities in Alzheimerʼs disease. Neurobiol Aging 2018; 61: 225-237
25 Solas M, Vela S, Smerdou C, Martisova E, Martínez-Valbuena I, Luquin MR, Ramírez MJ. JNK activation in Alzheimerʼs disease is driven by amyloid β and is associated with tau pathology. ACS Chem Neurosci 2023; 14: 1524-1534
26 Zhang T, Xia Y, Hu L, Chen D, Gan CL, Wang L, Mei Y, Lan G, Shui X, Tian Y, Li R, Zhang M, Lee TH. Death-associated protein kinase 1 mediates Aβ42 aggregation-induced neuronal apoptosis and tau dysregulation in Alzheimerʼs disease. Int J Biol Sci 2022; 18: 693-706
27 Yoshimura Y, Ichinose T, Yamauchi T. Phosphorylation of tau protein to sites found in Alzheimerʼs disease brain is catalyzed by Ca2+/calmodulin-dependent protein kinase II as demonstrated tandem mass spectrometry. Neurosci Lett 2003; 353: 185-188
28 Kumar P, Jha NK, Jha SK, Ramani K, Ambasta RK. Tau phosphorylation, molecular chaperones, and ubiquitin E3 ligase: clinical relevance in Alzheimerʼs disease. J Alzheimers Dis 2015; 43: 341-361
29 Nematullah M, Hoda MN, Khan F. Protein phosphatase 2A: A double-faced phosphatase of cellular system and its role in neurodegenerative disorders. Mol Neurobiol 2018; 55: 1750-1761
30 Liu C, Gotz J. How it all started: Tau and protein phosphatase 2A. J Alzheimers Dis 2013; 37: 483-494
31 Iqbal K, Liu F, Gong CX. Tau and neurodegenerative disease: the story so far. Nat Rev Neurol 2016; 12: 15-27
32 Yu UY, Yoo BC, Ahn JH. Regulatory B subunits of protein phosphatase 2A are involved in site-specific regulation of tau protein phosphorylation. Korean J Physiol Pharmacol 2014; 18: 155
33 Luo DJ, Feng Q, Wang ZH, Sun DS, Wang Q, Wang JZ, Liu GP. Knockdown of phosphotyrosyl phosphatase activator induces apoptosis via mitochondrial pathway and the attenuation by simultaneous tau hyperphosphorylation. J Neurochem 2014; 130: 816-825
34 Kimura T, Ishiguro K, Hisanaga S. Physiological and pathological phosphorylation of tau by Cdk5. Front Mol Neurosci 2014; 7: 65
35 Castro-Alvarez JF, Uribe-Arias SA, Mejía-Raigosa D, Cardona-Gómez GP. Cyclin-dependent kinase 5, a node protein in diminished tauopathy: A systems biology approach. Front Aging Neurosci 2014; 6: 232
36 Jiao B, Liu X, Zhou L, Wang MH, Zhou Y, Xiao T, Zhang W, Sun R, Waye MM, Tang B, Shen L. Polygenic analysis of late-onset Alzheimerʼs disease from mainland China. PLoS One 2015; 10: e0144898
37 Kwak SS, Washicosky KJ, Brand E, von Maydell D, Aronson J, Kim S, Capen DE, Cetinbas M, Sadreyev R, Ning S, Bylykbashi E, Xia W, Wagner SL, Choi SH, Tanzi RE, Kim DY. Amyloid-β42/40 ratio drives tau pathology in 3D human neural cell culture models of Alzheimerʼs disease. Nat Commun 2020; 11: 1377
38 Panza F, Solfrizzi V, Seripa D, Imbimbo BP, Lozupone M, Santamato A, Zecca C, Barulli MR, Bellomo A, Pilotto A, Daniele A, Greco A, Logroscino G. Tau-centric targets and drugs in clinical development for the treatment of Alzheimerʼs disease. Biomed Res Int 2016; 2016: 3245935
39 Spillantini MG, Goedert M. Tau pathology and neurodegeneration. Lancet Neurol 2013; 12: 609-622
40 Boutajangout A, Wisniewski T. Tau-based therapeutic approaches for Alzheimerʼs disease – A mini-review. Gerontology 2014; 60: 381-385
41 Boutajangout A, Sigurdsson EM, Krishnamurthy PK. Tau as a therapeutic target for Alzheimerʼs disease. Curr Alzheimer Res 2011; 8: 666-677
42 Rockenstein E, Ubhi K, Trejo M, Mante M, Patrick C, Adame A, Novak P, Jech M, Doppler E, Moessler H, Masliah E. Cerebrolysin efficacy in a transgenic model of tauopathy: Role in regulation of mitochondrial structure. BMC Neurosci 2014; 15: 90
43 Joshi YB, Giannopoulos PF, Pratico D. The 12/15-lipoxygenase as an emerging therapeutic target for Alzheimerʼs disease. Trends Pharmacol Sci 2015; 36: 181-186
44 Huang Y, Mucke L. Alzheimer mechanisms and therapeutic strategies. Cell 2012; 148: 1204-1222
45 Yoshiyama Y, Lee VMY, Trojanowski JQ. Therapeutic strategies for tau mediated neurodegeneration. J Neurol Neurosurg Psychiatry 2012; 84: 784-795
46 Luo Z, Yin F, Wang X, Kong L. Progress in approved drugs from natural product resources. Chin J Nat Med 2024; 22: 195-211
47 Zhang H, Chen W, Li Z, Huang Q, Wen J, Chang S, Pei H, Ma L, Li H. Huannao Yicong decoction ameliorates cognitive deficits in APP/PS1/tau triple transgenic mice by interfering with neurotoxic interaction of Aβ-tau. J Ethnopharmacol 2024; 318: 116985
48 Zhang Y, Huang N, Lu H, Huang J, Jin H, Shi J, Jin F. Icariin protects against sodium azide-induced neurotoxicity by activating the PI3K/Akt/GSK-3β signaling pathway. PeerJ 2020; 8: e8955
49 Ju IG, Kim N, Choi JG, Lee JK, Oh MS. Cuscutae Japonicae semen ameliorates memory dysfunction by rescuing synaptic damage in Alzheimerʼs disease models. Nutrients 2019; 11: 2591
50 Wang Z, Zhang Z, Liu J, Guo M, Li H. Panax Ginseng in the treatment of Alzheimerʼs disease and vascular dementia. J Ginseng Res 2023; 47: 506-514
51 Zhang KX, Sheng N, Ding PL, Zhang JW, Xu XQ, Wang YH. Danggui Shaoyao San alleviates early cognitive impairment in Alzheimerʼs disease mice through IRS1/GSK3β/Wnt3a-β-catenin pathway. Brain Behav 2024; 14: e70056
52 Wang Z, Yang Y, Liu M, Wei Y, Liu J, Pei H, Li H. Rhizoma Coptidis for Alzheimerʼs disease and vascular dementia: A literature review. Curr Vasc Pharmacol 2020; 18: 358-368
53 Wang YH, Ding PL, Zhang KX, Xu XQ, Li H. Correlation between regulation of intestinal flora by Danggui-Shaoyao-San and improvement of cognitive impairment in mice with Alzheimerʼs disease. Brain Behav 2024; 14: e70110
54 Zheng R, Shi S, Zhang Q, Yuan S, Guo T, Guo J, Jiang P. Molecular mechanisms of Huanglian Jiedu decoction in treating Alzheimerʼs disease by regulating microbiome via network pharmacology and molecular docking analysis. Front Cell Infect Microbiol 2023; 13: 1140945
55 Qi Y, Jing H, Cheng X, Yan T, Xiao F, Wu B, Bi K, Jia Y. Alpinia oxyphylla-Schisandra chinensis herb pair alleviates amyloid-β induced cognitive deficits via PI3K/Akt/Gsk-3β/CREB pathway. Neuromolecular Med 2020; 22: 370-383
56 Su SJ, Chen Y, Yang HY, Liu HN, Han L, Wang H, Li WR, Wang Q. [Exploration on mechanism of Polygalae Radix and Acori Tatarinowii Rhizoma in treating Alzheimerʼs disease based on network pharmacology and experimental verification]. Zhongguo Zhong Yao Za Zhi 2022; 47: 3348-3360 [Article in Chinese]
57 Jones WP, Kinghorn AD. Extraction of plant secondary metabolites. Methods Mol Biol 2012; 864: 341-366
58 Bagade SB, Patil M. Recent advances in microwave assisted extraction of bioactive compounds from complex herbal samples: A review. Crit Rev Anal Chem 2021; 5: 138-149
59 Nadar SS, Rao P, Rathod VK. Enzyme assisted extraction of biomolecules as an approach to novel extraction technology: A review. Food Res Int 2018; 108: 309-330
60 Mikšovsky P, Kornpointner C, Parandeh Z, Goessinger M, Bica-Schröder K, Halbwirth H. Enzyme-assisted supercritical fluid extraction of flavonoids from apple pomace (Malus×domestica). ChemSusChem 2024; 17: e202301094
61 Wu N, Xie H, Fang Y, Liu Y, Xi X, Chu Q, Dong G, Lan T, Wei Y. Isolation and purification of alkaloids from lotus leaves by ionic-liquid-modified high-speed countercurrent chromatography. J Sep Sci 2018; 41: 571-577
62 Brusotti G, Cesari I, Dentamaro A, Caccialanza G, Massolini G. Isolation and characterization of bioactive compounds from plant resources: the role of analysis in the ethnopharmacological approach. J Pharm Biomed Anal 2014; 87: 218-228
63 Mullowney MW, Duncan KR, Elsayed SS, Garg N, van der Hooft JJJ, Martin NI, Meijer D, Terlouw BR, Biermann F, Blin K, Durairaj J, Gorostiola González M, Helfrich EJN, Huber F, Leopold-Messer S, Rajan K, de Rond T, van Santen JA, Sorokina M, Balunas MJ, Beniddir MA, van Bergeijk DA, Carroll LM, Clark CM, Clevert DA, Dejong CA, Du C, Ferrinho S, Grisoni F, Hofstetter A, Jespers W, Kalinina OV, Kautsar SA, Kim H, Leao TF, Masschelein J, Rees ER, Reher R, Reker D, Schwaller P, Segler M, Skinnider MA, Walker AS, Willighagen EL, Zdrazil B, Ziemert N, Goss RJM, Guyomard P, Volkamer A, Gerwick WH, Kim HU, Müller R, van Wezel GP, van Westen GJP, Hirsch AKH, Linington RG, Robinson SL, Medema MH. Artificial intelligence for natural product drug discovery. Nat Rev Drug Discov 2023; 22: 895-916
64 Rios-Martinez C, Bhattacharya N, Amini AP, Crawford L, Yang KK. Deep self-supervised learning for biosynthetic gene cluster detection and product classification. PLoS Comput Biol 2023; 19: e1011162
65 Sakai M, Nagayasu K, Shibui N, Andoh C, Takayama K, Shirakawa H, Kaneko S. Prediction of pharmacological activities from chemical structures with graph convolutional neural networks. Sci Rep 2021; 11: 525
66 Ekiert HM, Szopa A. Biological activities of natural products. Molecules 2020; 25: 5769
67 Li Y, Dai S, Huang N, Wu J, Yu C, Luo Y. Icaritin and icariin reduce p-Tau levels in a cell model of Alzheimerʼs disease by downregulating glycogen synthase kinase 3β . Biotechnol Appl Biochem 2022; 69: 355-363
68 Hong XP, Chen T, Yin NN, Han YM, Yuan F, Duan YJ, Shen F, Zhang YH, Chen ZB. Puerarin ameliorates D-galactose induced enhanced hippocampal neurogenesis and tau hyperphosphorylation in rat brain. J Alzheimers Dis 2016; 51: 605-617
69 Nakajima A, Aoyama Y, Nguyen TT, Shin EJ, Kim HC, Yamada S, Nakai T, Nagai T, Yokosuka A, Mimaki Y, Ohizumi Y, Yamada K. Nobiletin, a citrus flavonoid, ameliorates cognitive impairment, oxidative burden, and hyperphosphorylation of tau in senescence-accelerated mouse. Behav Brain Res 2013; 250: 351-360
70 Shengkai D, Yazhen S. Flavonoids from stems and leaves of Scutellaria baicalensis Georgi regulate the brain tau hyperphosphorylation at multiple sites induced by composited Aβ in rats. CNS Neurol Disord Drug Targets 2022; 21: 367-374
71 Hu X, Teng S, He J, Sun X, Du M, Kou L, Wang X. Pharmacological basis for application of scutellarin in Alzheimerʼs disease: Antioxidation and antiapoptosis. Mol Med Rep 2018; 18: 4289-4296
72 Sun XY, Li LJ, Dong QX, Zhu J, Huang YR, Hou SJ, Yu XL, Liu RT. Rutin prevents tau pathology and neuroinflammation in a mouse model of Alzheimerʼs disease. J Neuroinflammation 2021; 18: 131
73 Qi Y, Guo L, Jiang Y, Shi Y, Sui H, Zhao L. Brain delivery of quercetin-loaded exosomes improved cognitive function in AD mice by inhibiting phosphorylated tau-mediated neurofibrillary tangles. Drug Deliv 2020; 27: 745-755
74 Alexander C, Parsaee A, Vasefi M. Polyherbal and multimodal treatments: Kaempferol- and quercetin-rich herbs alleviate symptoms of Alzheimerʼs disease. Biology (Basel) 2023; 12: 1453
75 Zeng K, Li M, Hu J, Mahaman YAR, Bao J, Huang F, Xia Y, Liu X, Wang Q, Wang JZ, Yang Y, Liu R, Wang X. Ginkgo biloba extract EGb761 attenuates hyperhomocysteinemia-induced AD like tau hyperphosphorylation and cognitive impairment in rats. Curr Alzheimer Res 2018; 15: 89-99
76 Zhao B, Wang Y, Liu R, Jia XL, Hu N, An XW, Zheng CG, Chen C, Sun HT, Chen F, Wang JJ, Li XH. Rutaecarpine ameliorated high sucrose-induced Alzheimerʼs disease like pathological and cognitive impairments in mice. Rejuvenation Res 2021; 24: 181-190
77 He W, Wang C, Chen Y, He Y, Cai Z. Berberine attenuates cognitive impairment and ameliorates tau hyperphosphorylation by limiting the self-perpetuating pathogenic cycle between NF-κB signaling, oxidative stress and neuroinflammation. Pharmacol Rep 2017; 69: 1341-1348
78 Chen Y, Chen Y, Liang Y, Chen H, Ji X, Huang M. Berberine mitigates cognitive decline in an Alzheimerʼs disease mouse model by targeting both tau hyperphosphorylation and autophagic clearance. Biomed Pharmacother 2020; 121: 109670
79 Zhang Q, Wang J, Zhu L, Jiang SJ, Liu J, Wang LX, Qin XH. Ligustrazine attenuates hyperhomocysteinemia-induced Alzheimer-like pathologies in rats. Curr Med Sci 2021; 41: 548-554
80 Chen L, Pan H, Bai Y, Li H, Yang W, Lin ZX, Cui W, Xian YF. Gelsemine, a natural alkaloid extracted from Gelsemium elegans Benth. alleviates neuroinflammation and cognitive impairments in Aβ oligomer-treated mice. Psychopharmacology (Berl) 2020; 237: 2111-2124
81 Li HQ, Ip SP, Yuan QJ, Zheng GQ, Tsim KKW, Dong TTX, Lin G, Han Y, Liu Y, Xian YF, Lin ZX. Isorhynchophylline ameliorates cognitive impairment via modulating amyloid pathology, tau hyperphosphorylation and neuroinflammation: Studies in a transgenic mouse model of Alzheimerʼs disease. Brain Behav Immun 2019; 82: 264-278
82 Wongjaikam S, Nopparat C, Boontem P, Panmanee J, Thasana N, Shukla M, Govitrapong P. Huperzine a regulates the physiological homeostasis of amyloid precursor protein proteolysis and tau protein conformation-a computational and experimental investigation. Biology (Basel) 2024; 13: 518
83 Wu JJ, Yang Y, Wan Y, Xia J, Xu JF, Zhang L, Liu D, Chen L, Tang F, Ao H, Peng C. New insights into the role and mechanisms of ginsenoside Rg1 in the management of Alzheimerʼs disease. Biomed Pharmacother 2022; 152: 113207
84 Ye X, Shao S, Wang Y, Su W. Ginsenoside Rg2 alleviates neurovascular damage in 3xTg-AD mice with Alzheimerʼs disease through the MAPK-ERK pathway. J Chem Neuroanat 2023; 133: 102346
85 Zhao HH, Di J, Liu WS, Liu HL, Lai H, Lü YL. Involvement of GSK3 and PP2A in ginsenoside Rb1′s attenuation of aluminum-induced tau hyperphosphorylation. Behav Brain Res 2013; 241: 228-234
86 Zhang X, Shi M, Ye R, Wang W, Liu X, Zhang G, Han J, Zhang Y, Wang B, Zhao J, Hui J, Xiong L, Zhao G. Ginsenoside Rd attenuates tau protein phosphorylation via the PI3K/AKT/GSK-3β pathway after transient forebrain ischemia. Neurochem Res 2014; 39: 1363-1373
87 Huang XB, Chen YJ, Chen WQ, Wang NQ, Wu XL, Liu Y. Neuroprotective effects of tenuigenin on neurobehavior, oxidative stress, and tau hyperphosphorylation induced by intracerebroventricular streptozotocin in rats. Brain Circ 2018; 4: 24-32
88 Zhang YM, Zheng T, Huang TT, Gu PP, Gou LS, Ma TF, Liu YW. Sarsasapogenin attenuates Alzheimer-like encephalopathy in diabetes. Phytomedicine 2021; 91: 153686
89 Lee TH, Park S, You MH, Lim JH, Min SH, Kim BM. A potential therapeutic effect of saikosaponin C as a novel dual-target anti-Alzheimer agent. J Neurochem 2016; 136: 1232-1245
90 Liu Y, Liu Z, Wei M, Hu M, Yue K, Bi R, Zhai S, Pi Z, Song F, Liu Z. Pharmacodynamic and urinary metabolomics studies on the mechanism of Schisandra polysaccharide in the treatment of Alzheimerʼs disease. Food Funct 2019; 10: 432-447
91 Dong Q, Li Z, Zhang Q, Hu Y, Liang H, Xiong L. Astragalus mongholicus Bunge (Fabaceae): Bioactive compounds and potential therapeutic mechanisms against Alzheimerʼs disease. Front Pharmacol 2022; 13: 924429
92 Zhang Q, Xia Y, Luo H, Huang S, Wang Y, Shentu Y, Mahaman YAR, Huang F, Ke D, Wang Q, Liu R, Wang JZ, Zhang B, Wang X. Codonopsis pilosula polysaccharide attenuates tau hyperphosphorylation and cognitive impairments in hTau infected mice. Front Mol Neurosci 2018; 11: 437
93 He Y, Wang Y, Li X, Qi Y, Qu Z, Hu Y. Lycium Barbarum polysaccharides improves cognitive functions in ICV-STZ-induced Alzheimerʼs disease mice model by improving the synaptic structural plasticity and regulating IRS1/PI3K/AKT signaling pathway. Neuromolecular Med 2024; 26: 15
94 Zhou X, Zhang Y, Jiang Y, Zhou C, Ling Y. Poria cocos polysaccharide attenuates damage of nervus in Alzheimerʼs disease rat model induced by D-galactose and aluminum trichloride. Neuroreport 2021; 32: 727-737
95 Feng CZ, Cao L, Luo D, Ju LS, Yang JJ, Xu XY, Yu YP. Dendrobium polysaccharides attenuate cognitive impairment in senescence-accelerated mouse prone 8 mice via modulation of microglial activation. Brain Res 2019; 1704: 1-10
96 Moorthy H, Ramesh M, Padhi D, Baruah P, Govindaraju T. Polycatechols inhibit ferroptosis and modulate tau liquid-liquid phase separation to mitigate Alzheimerʼs disease. Mater Horiz 2024; 11: 3082-3089
97 Zang WB, Wei HL, Zhang WW, Ma W, Li J, Yao Y. Curcumin hybrid molecules for the treatment of Alzheimerʼs disease: Structure and pharmacological activities. Eur J Med Chem 2024; 265: 116070
98 Cha J, Yun JH, Choi JH, Lee JH, Choi BT, Shin HK. Preclinical evidence and underlying mechanisms of Polygonum multiflorum and its chemical constituents against cognitive impairments and Alzheimerʼs disease. J Pharmacopuncture 2024; 27: 70-81
99 Wu J, Hu W, Gong Y, Wang P, Tong L, Chen X, Chen Z, Xu X, Yao W, Zhang W, Huang C. Current pharmacological developments in 2, 3, 4′,5-tetrahydroxystilbene 2-O-β-D-glucoside (TSG). Eur J Pharmacol 2017; 811: 21-29
100 Luo K, Wang Y, Chen WS, Feng X, Liao Y, Chen S, Liu Y, Liao C, Chen M, Ao L. Treatment combining focused ultrasound with Gastrodin alleviates memory deficit and neuropathology in an Alzheimerʼs disease-like experimental mouse model. Neural Plast 2022; 2022: 5241449
101 Zhang B, Li Q, Chu X, Sun S, Chen S. Salidroside reduces tau hyperphosphorylation via up-regulating GSK-3β phosphorylation in a tau transgenic Drosophila model of Alzheimerʼs disease. Transl Neurodegener 2016; 5: 21
102 Gao L, Wang D, Ren J, Tan X, Chen J, Kong Z, Nie Y, Yan M. Acteoside ameliorates learning and memory impairment in APP/PS1 transgenic mice by increasing Aβ degradation and inhibiting tau hyperphosphorylation. Phytother Res 2024; 38: 1735-1744
103 Zhao ZY, Zhang YQ, Zhang YH, Wei XZ, Wang H, Zhang M, Yang ZJ, Zhang CH. The protective underlying mechanisms of Schisandrin on SH-SY5Y cell model of Alzheimerʼs disease. J Toxicol Environ Health A 2019; 82: 1019-1026
104 Qu C, Li QP, Su ZR, Ip SP, Yuan QJ, Xie YL, Xu QQ, Yang W, Huang YF, Xian YF, Lin ZX. Nano-Honokiol ameliorates the cognitive deficits in TgCRND8 mice of Alzheimerʼs disease via inhibiting neuropathology and modulating gut microbiota. J Adv Res 2021; 35: 231-243
105 Singh L, Bhatti R. Signaling pathways involved in the neuroprotective effect of Osthole: Evidence and mechanisms. Mol Neurobiol 2024; 61: 1100-1118
106 Turkez H, Arslan ME, Barboza JN, Kahraman CY, de Sousa DP, Mardinoğlu A. Therapeutic potential of ferulic acid in Alzheimerʼs disease. Curr Drug Deliv 2022; 19: 860-873
107 Zhao Y, Deng H, Li K, Wang L, Wu Y, Dong X, Wang X, Chen Y, Xu Y. Trans-cinnamaldehyde improves neuroinflammation-mediated NMDA receptor dysfunction and memory deficits through blocking NF-κB pathway in presenilin1/2 conditional double knockout mice. Brain Behav Immun 2019; 82: 45-62
108 Ma D, Luo Y, Huang R, Zhao Z, Wang Q, Li L, Zhang L. Cornel iridoid glycoside suppresses tau hyperphosphorylation and aggregation in a mouse model of tauopathy through increasing activity of PP2A. Curr Alzheimer Res 2019; 16: 1316-1331
109 Yang C, Li X, Gao W, Wang Q, Zhang L, Li Y, Li L, Zhang L. Cornel iridoid glycoside inhibits tau hyperphosphorylation via regulating cross-talk between GSK-3β and PP2A signaling. Front Pharmacol 2018; 9: 682
110 Sun X, Li S, Xu L, Wang H, Ma Z, Fu Q, Qu R, Ma S. Paeoniflorin ameliorates cognitive dysfunction via regulating SOCS2/IRS-1 pathway in diabetic rats. Physiol Behav 2017; 174: 162-169
111 Lin L, Jadoon SS, Liu SZ, Zhang RY, Li F, Zhang MY, Ai-Hua T, You QY, Wang P. Tanshinone IIA ameliorates spatial learning and memory deficits by inhibiting the activity of ERK and GSK-3β . J Geriatr Psychiatry Neurol 2019; 32: 152-163
112 Zhao S, Zhang L, Yang C, Li Z, Rong S. Procyanidins and Alzheimerʼs disease. Mol Neurobiol 2019; 56: 5556-5567
113 Zhao X, Li S, Gaur U, Zheng W. Artemisinin improved neuronal functions in Alzheimerʼs disease animal model 3 xtg mice and neuronal cells via stimulating the ERK/CREB signaling pathway. Aging Dis 2020; 11: 801-819
114 Xu QQ, Su ZR, Hu Z, Yang W, Xian YF, Lin ZX. Patchouli alcohol ameliorates the learning and memory impairments in an animal model of Alzheimerʼs disease via modulating SIRT1. Phytomedicine 2022; 106: 154441
115 Yang C, Su C, Iyaswamy A, Krishnamoorthi SK, Zhu Z, Yang S, Tong BC, Liu J, Sreenivasmurthy SG, Guan X, Kan Y, Wu AJ, Huang AS, Tan J, Cheung K, Song J, Li M. Celastrol enhances transcription factor EB (TFEB)-mediated autophagy and mitigates tau pathology: Implications for Alzheimerʼs disease therapy. Acta Pharm Sin B 2022; 12: 1707-1722
116 Lauretti E, Dincer O, Praticò D. Glycogen synthase kinase-3 signaling in Alzheimerʼs disease. Biochim Biophys Acta Mol Cell Res 2020; 1867: 118664
117 Forlenza OV, de Paula VJ, Machado-Vieira R, Diniz BS, Gattaz WF. Does lithium prevent Alzheimerʼs disease?. Drugs Aging 2012; 29: 335-342
118 He DL, Zhang XY, Su JY, Zhang Q, Zhao LX, Wu TY, Ren H, Jia RJ, Lei XF, Hou WJ, Sun WG, Fan YG, Wang ZY. Identification of AS1842856 as a novel small-molecule GSK3α/β inhibitor against Tauopathy by accelerating GSK3α/β exocytosis. Aging Cell 2025; 24: e14336
119 van Eersel J, Ke YD, Liu X, Delerue F, Kril JJ, Götz J, Ittner LM. Sodium selenate mitigates tau pathology, neurodegeneration, and functional deficits in Alzheimerʼs disease models. Proc Natl Acad Sci U S A 2010; 107: 13888-13893
120 Vivash L, Malpas CB, Hovens CM, Brodtmann A, Collins S, Macfarlane S, Velakoulis D, OʼBrien TJ. Sodium selenate as a disease-modifying treatment for mild-moderate Alzheimerʼs disease: an open-label extension study. BMJ Neurol Open 2021; 3: e000223
121 Najmi A, Javed SA, Al Bratty M, Alhazmi HA. Modern approaches in the discovery and development of plant-based natural products and their analogues as potential therapeutic agents. Molecules 2022; 27: 349
122 Thomford NE, Senthebane DA, Rowe A, Munro D, Seele P, Maroyi A, Dzobo K. Natural products for drug discovery in the 21st century: Innovations for novel drug discovery. Int J Mol Sci 2018; 19: 1578
123 Zhang L, Song J, Kong L, Yuan T, Li W, Zhang W, Hou B, Lu Y, Du G. The strategies and techniques of drug discovery from natural products. Pharmacol Ther 2020; 216: 107686