Epigallocatechin-3-gallate Alleviates Cognitive Deficits in APP/PS1 Mice

Abstract

Alzheimer’s disease (AD) shows cognitive impairments in clinic, which is multifactorial with different etiopathogenic mechanisms such as Aβ deposition, neuroinflammation and neuronal dystrophy involved. Therefore, multi-targets drugs with neuroprotective, anti-amyloidogenic and anti-inflammatory properties will be effective in AD treatment. Epigallocatechin-3-gallate (EGCG) possesses a broad spectrum of pharmacological activities in the prevention and treatment of multiple neurodegenerative diseases. In the present study, we showed that oral administration of EGCG (50 mg/kg) for 4 months significantly attenuated the cognitive deficits in APP/PS1 transgenic mice, which served as AD model. Moreover, EGCG induced an improvement in dendritic integrity and expression levels of synaptic proteins in the brain of APP/PS1 mice. And EGCG exerted obvious anti-inflammatory effects, which was manifested by alleviating microglia activation, decreasing pro-inflammatory cytokine (IL-1β) and increasing anti-inflammatory cytokines (IL-10, IL-13). Furthermore, β-amyloid (Aβ) plaques were markedly reduced in the hippocampus of 6-month old APP/PS1 mice after EGCG treatment. In conclusion, these findings indicate that EGCG improves AD-like cognitive impairments through neuroprotective, anti-amyloidogenic and anti-inflammatory effects, thus is a promising therapeutic candidate for AD.

Keywords

Alzheimer’s disease / cognitive impairments / epigallocatechin-3-gallate / anti-inflammation / β-amyloid

References

[1] IqbalK, Grundke-IqbalI, ZaidiT, et al.. Defective brain microtubule assembly in Alzheimer’s disease. Lancet, 1986, 2(8504): 421-426

[2] BjorklundG, AasethJ, DadarM, et al.. Molecular Targets in Alzheimer’s Disease. Mol Neurobiol, 2019, 56(10): 7032-7044

[3] LongJM, HoltzmanDM. Alzheimer Disease: An Update on Pathobiology and Treatment Strategies. Cell, 2019, 179(2): 312-339

[4] VassarR, KovacsDM, YanR, et al.. The beta-secretase enzyme BACE in health and Alzheimer’s disease: regulation, cell biology, function, and therapeutic potential. J Neurosci, 2009, 29(41): 12 787-12 794

[5] YanR, VassarR. Targeting the beta secretase BACE1 for Alzheimer’s disease therapy. Lancet Neurol, 2014, 13(3): 319-329

[6] De StrooperB, VassarR, GoldeT. The secretases: enzymes with therapeutic potential in Alzheimer disease. Nat Rev Neurol, 2010, 6(2): 99-107

[7] IqbalK, AlonsoA C, Grundke-IqbalI. Cytosolic abnormally hyperphosphorylated tau but not paired helical filaments sequester normal MAPs and inhibit microtubule assembly. J Alzheimers Dis, 2008, 14(4): 365-370

[8] IqbalK, Grundke-IqbalI. Ubiquitination and abnormal phosphorylation of paired helical filaments in Alzheimer’s disease. Mol Neurobiol, 1991, 5(2–4): 399-410

[9] IqbalK, Grundke-IqbalI. Alzheimer neurofibrillary degeneration: significance, etiopathogenesis, therapeutics and prevention. J Cell Mol Med, 2008, 12(1): 38-55

[10] AlonsoAC, ZaidiT, Grundke-IqbalI, et al.. Role of abnormally phosphorylated tau in the breakdown of microtubules in Alzheimer disease. Proc Natl Acad Sci USA, 1994, 91(12): 5562-5566

[11] HooverBR, ReedMN, SuJ, et al.. Tau Mislocalization to Dendritic Spines Mediates Synaptic Dysfunction Independently of Neurodegeneration. Neuron, 2010, 68(6): 1067-1081

[12] DominguesC, da CruzESOAB, HenriquesAG. Impact of Cytokines and Chemokines on Alzheimer’s Disease Neuropathological Hallmarks. Curr Alzheimer Res, 2017, 14(8): 870-882

[13] McGeerPL, McGeerEG. The amyloid cascade-inflammatory hypothesis of Alzheimer disease: implications for therapy. Acta Neuropathol, 2013, 126(4): 479-497

[14] HanQQ, ShenTT, WangF, et al.. Preventive and Therapeutic Potential of Vitamin C in Mental Disorders. Curr Med Sci, 2018, 38(1): 1-10

[15] AgostinhoP, CunhaRA, OliveiraC. Neuroinflammation, oxidative stress and the pathogenesis of Alzheimer’s disease. Curr Pharm Des, 2010, 16(25): 2766-1678

[16] DzambaD, HarantovaL, ButenkoO, et al.. Glial Cells — The Key Elements of Alzheimer’s Disease. Curr Alzheimer Res, 2016, 13(8): 894-911

[17] GuerrieroF, SgarlataC, FrancisM, et al.. Neuroinflammation, immune system and Alzheimer disease: searching for the missing link. Aging Clin Exp Res, 2017, 29(5): 821-831

[18] MedaL, CassatellaMA, SzendreiGI, et al.. Activation of microglial cells by beta-amyloid protein and interferon-gamma. Nature, 1995, 374(6523): 647-650

[19] Meraz-RiosMA, Toral-RiosD, Franco-BocanegraD, et al.. Inflammatory process in Alzheimer’s Disease. Front Integr Neurosci, 2013, 7: 59

[20] MoralesI, Guzman-MartinezL, Cerda-TroncosoC, et al.. Neuroinflammation in the pathogenesis of Alzheimer’s disease. A rational framework for the search of novel therapeutic approaches. Front Cell Neurosci, 2014, 8: 112

[21] CanterRG, PenneyJ, TsaiLH. The road to restoring neural circuits for the treatment of Alzheimer’s disease. Nature, 2016, 539(7628): 187-196

[22] QuerfurthHW, LaFerlaFM. Alzheimer’s disease. N Engl J Med, 2010, 362(4): 329-344

[23] GuoS, BezardE, ZhaoB. Protective effect of green tea polyphenols on the SH-SY5Y cells against 6-OHDA induced apoptosis through ROS-NO pathway. Free Radical Biol Med, 2005, 39(5): 682-695

[24] NanjoF, GotoK, SetoR, et al.. Scavenging effects of tea catechins and their derivatives on 1,1-diphenyl-2-picrylhydrazyl radical. Free Radical Biol Med, 1996, 21(6): 895-902

[25] SinghR, AkhtarN, HaqqiTM. Green tea polyphenol epigallocatechin-3-gallate: inflammation and arthritis. Life Sci, 2010, 86(25–26): 907-918

[26] UnnoK, TakabayashiF, KishidoT, et al.. Suppressive effect of green tea catechins on morphologic and functional regression of the brain in aged mice with accelerated senescence (SAMP10). Exp Gerontol, 2004, 39(7): 1027-1034

[27] UnnoK, TakabayashiF, YoshidaH, et al.. Daily consumption of green tea catechin delays memory regression in aged mice. Biogerontology, 2007, 8(2): 89-95

[28] Rezai-ZadehK, ArendashGW, HouH, et al.. Green tea epigallocatechin-3-gallate (EGCG) reduces beta-amyloid mediated cognitive impairment and modulates tau pathology in Alzheimer transgenic mice. Brain Res, 2008, 1214: 177-187

[29] Rezai-ZadehK, ShytleD, SunN, et al.. Green tea epigallocatechin-3-gallate (EGCG) modulates amyloid precursor protein cleavage and reduces cerebral amyloidosis in Alzheimer transgenic mice. J Neurosci, 2005, 25(38): 8807-8814

[30] VorheesCV, WilliamsMT. Morris water maze: procedures for assessing spatial and related forms of learning and memory. Nat Protoc, 2006, 1(2): 848-858

[31] DingY, QiaoAM, WangZQ, et al.. Retinoic Acid Attenuates beta-Amyloid Deposition and Rescues Memory Deficits in an Alzheimer’s Disease Transgenic Mouse Model. J Neurosci, 2008, 28(45): 11 622-11 634

[32] CaoDF, LuHL, LewisTL, et al.. Intake of sucrose-sweetened water induces insulin resistance and exacerbates memory deficits and amyloidosis in a transgenic mouse model of Alzheimer disease. J Biol Chem, 2007, 282(50): 36 275-36 282

[33] KurtMA, DaviesDC, KiddM, et al.. Hyperphosphorylated tau and paired helical filament-like structures in the brains of mice carrying mutant amyloid precursor protein and mutant presenilin-1 transgenes. Neurobiol Dis, 2003, 14(1): 89-97

[34] ArabH, MahjoubS, Hajian-TilakiK, et al.. The effect of green tea consumption on oxidative stress markers and cognitive function in patients with Alzheimer’s disease: A prospective intervention study. Caspian J Intern Med, 2016, 7(3): 188-194

[35] ChanDKY, MellickGD, et al.. Genetic and environmental risk factors and their interactions for Parkinson’s disease in a Chinese population. J Clin Neurosci, 2003, 10(3): 313-315

[36] KuriyamaS, HozawaA, OhmoriK, et al.. Green tea consumption and cognitive function: a cross-sectional study from the Tsurugaya Project 1. Am J Clin Nutr, 2006, 83(2): 355-361

[37] RitchieK, LovestoneS. The dementias. Lancet, 2002, 360(9347): 1759-1766

[38] GrinbergLN, NewmarkH, KitrosskyN, et al.. Protective effects of tea polyphenols against oxidative damage to red blood cells. Biochem Pharmacol, 1997, 54(9): 973-978

[39] van AckerSA, van den BergDJ, TrompMN, et al.. Structural aspects of antioxidant activity of flavonoids. Free Radical Biol Med, 1996, 20(3): 331-342

[40] OkelloEJ, LeylabiR, McDougallGJ. Inhibition of acetylcholinesterase by green and white tea and their simulated intestinal metabolites. Food Funct, 2012, 3(6): 651-661

[41] QinXY, ChengY, YuLC. Potential protection of green tea polyphenols against intracellular amyloid beta-induced toxicity on primary cultured prefrontal cortical neurons of rats. Neurosci Lett, 2012, 513(2): 170-173

[42] SinghNA, MandalAK, KhanZA. Potential neuroprotective properties of epigallocatechin-3-gallate (EGCG). Nutrition J, 2016, 15(1): 60

[43] HaqueAM, HashimotoM, KatakuraM, et al.. Long-term administration of green tea catechins improves spatial cognition learning ability in rats. J Nutr, 2006, 136(4): 1043-1047

[44] ErbaD, RisoP, BordoniA, et al.. Effectiveness of moderate green tea consumption on antioxidative status and plasma lipid profile in humans. J Nutr Biochem, 2005, 16(3): 144-149

[45] PanzaVSP, WazlawikE, SchuetzGR, et al.. Consumption of green tea favorably affects oxidative stress markers in weight-trained men. Nutrition, 2008, 24(5): 433-442

[46] SartorL, PezzatoE, GarbisaS. (−)Epigallocatechin-3-gallate inhibits leukocyte elastase: potential of the phyto-factor in hindering inflammation, emphysema, and invasion. J Leukocyte Biol, 2002, 71(1): 73-79

[47] DonaM, Dell’AicaI, CalabreseF, et al.. Neutrophil, restraint by green tea: Inhibition of inflammation, associated angiogenesis, and pulmonary fibrosis. J Immunol, 2003, 170(8): 4335-4341

[48] SanY B, OlveraRA, SinghV, et al.. Epigallocatechin-3-Gallate Inhibition of Myeloperoxidase and Its Counter-Regulation by Dietary Iron and Lipocalin 2 in Murine Model of Gut Inflammation. Am J Pathol, 2016, 186(4): 912-926

[49] BanJY, JeonSY, BaeK, et al.. Catechin and epicatechin from Smilacis chinae rhizome protect cultured rat cortical neurons against amyloid beta protein (25–35)-induced neurotoxicity through inhibition of cytosolic calcium elevation. Life Sci, 2006, 79(24): 2251-2259

[50] KohSH, LeeSM, KimHY, et al.. The effect of epigallocatechin gallate on suppressing disease progression of ALS model mice. Neurosci Lett, 2006, 395(2): 103-107

[51] ReznichenkoL, AmitT, YoudimMB, et al.. Green tea polyphenol (−)-epigallocatechin-3-gallate induces neurorescue of long-term serum-deprived PC12 cells and promotes neurite outgrowth. J Neurochem, 2005, 93(5): 1157-1167