Resveratrol in Alzheimer's disease: a review of pathophysiology and therapeutic potential

ABSTRACT

Background: Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive and irreversible loss of cognitive function. The presence of senile plaques is one of the pathological markers of the disease and is associated with the onset of neuroinflammatory mechanisms. The exact pathophysiology of AD has not been completely understood, and there are no curative therapies yet. Resveratrol (3,5,4'-trihydroxy-trans-stilbene) is a polyphenol that is noted for its antioxidant and anti-inflammatory properties. Objective: To review the role of resveratrol in the pathophysiological aspects of AD. Methods: This study carried out a literature review using PubMed/Medline, Virtual Health Library (VHL), Web of Sciences, SCOPUS and the Cochrane Library databases. Original research articles, describing both in vitro and in vivo experiments, published between 2008 and 2018, were included. Results: We identified 667 articles, of which 619 were excluded because they were repeated or did not follow the inclusion criteria. The present study includes the remaining 48 articles. Discussion: Resveratrol demonstrates beneficial and protective effects in AD models and seems to provide a promising therapeutic alternative. Conclusion: Although resveratrol appears to mitigate some pathophysiological aspects of AD, further studies are needed to prove the safety and efficacy of this compound in humans.

RESUMO

Introdução: A doença de Alzheimer (DA) é neurodegenerativa e caracterizada por perda progressiva e irreversível da função cognitiva. A presença de placas senis é um dos marcadores patológicos da doença e está associada ao aparecimento de mecanismos neuroinflamatórios. A fisiopatologia exata da DA ainda não é completamente compreendida, e ainda não existem terapias curativas. O resveratrol (3,5,4'-trihidroxi-trans-estilbeno) é um polifenol conhecido por suas propriedades antioxidantes e anti-inflamatórias. Objetivo: Revisar o papel do resveratrol nos aspectos fisiopatológicos da DA. Métodos: Este estudo realizou uma revisão narrativa da literatura a partir das bases de dados PubMed/Medline, Biblioteca Virtual em Saúde (BVS), Web of Science, SCOPUS e Cochrane Library. Foram incluídos artigos originais, realizados in vitro e in vivo, publicados entre 2008 e 2018. Resultados: Foram identificados 667 artigos, dos quais 619 foram excluídos por estarem repetidos ou não se enquadrarem nos critérios de inclusão. O presente estudo inclui os 48 artigos restantes. Discussão: O resveratrol demonstra efeitos benéficos e protetores em modelos de DA, bem como parece fornecer uma alternativa terapêutica promissora. Conclusão: Embora o resveratrol pareça atenuar alguns aspectos fisiopatológicos da DA, são necessários mais estudos para comprovar a segurança e a eficácia deste composto em seres humanos.

Keywords:

amyloid - sirtuin 1 - antioxidants - polyphenols - nutraceuticals

Palavras-chave:

amiloide - sirtuína 1 - antioxidantes - polifenóis - nutracêuticos

Publication History

Received: 04 December 2019

Accepted: 17 January 2020

Article published online:
13 June 2023

• References

• 1 CristÒfol R, Porquet D, Corpas R, Coto-Montes A, Serret J, Camins A, et al. Neurons from senescence-accelerated SAMP8 mice are protected against frailty by the sirtuin 1 promoting agents melatonin and resveratrol: Melatonin and resveratrol protect SAMP8 neurons. J Pineal Res. 2012 Apr;52(3):271-81. https://doi.org/10.1111/j.1600-079X.2011.00939.x
• 2 Feng X, Liang N, Zhu D, Gao Q, Peng L, Dong H, et al. Resveratrol Inhibits β-Amyloid-Induced Neuronal Apoptosis through Regulation of SIRT1-ROCK1 Signaling Pathway. PLoS One. 2013 Mar;8(3):e59888. https://doi.org/10.1371/journal.pone.0059888
• 3 Chiang MC, Nicol CJ, Cheng YC. Resveratrol activation of AMPK-dependent pathways is neuroprotective in human neural stem cells against amyloid-β-induced inflammation and oxidative stress. Neurochem Int. 2018 May;115:1-10. https://doi.org/10.1016/j.neuint.2017.10.002
• 4 Dong YT, Cao K, Tan LC, Wang XL, Qi XL, Xiao Y, et al. Stimulation of SIRT1 attenuates the level of oxidative stress in the brains of APP/PS1 double transgenic mice and in primary neurons exposed to oligomers of the amyloid-β peptide. J Alzheimers Dis. 2018 Apr;63(1):283-301. https://doi.org/10.3233/JAD-171020
• 5 Zhang J, Feng X, Wu J, Xu H, Li G, Zhu D, et al. Neuroprotective effects of resveratrol on damages of mouse cortical neurons induced by β-amyloid through activation of SIRT1/Akt1 pathway: SIRT1/Akt1 mediates neuroprotective effects of resveratrol. BioFactors. 2014 Mar/Apr;40(2):258-67. https://doi.org/10.1002/biof.1149
• 6 Granzotto A, Zatta P. Resveratrol acts not through anti-aggregative pathways but mainly via its scavenging properties against Aβ and Aβ -metal complexes toxicity. PLoS One. 2011 Jun;6(6):e21565. https://doi.org/10.1371/journal.pone.0021565
• 7 Karthick C, Periyasamy S, Jayachandran KS, Anusuyadevi M. Intrahippocampal administration of ibotenic acid induced Cholinergic Dysfunction via NR2A/NR2B expression: implications of resveratrol against Alzheimer Disease pathophysiology. Front Mol Neurosci. 2016 Apr;26(9):28. https://doi.org/10.3389/fnmol.2016.00028
• 8 Yao Y, Li J, Niu Y, Yu JQ, Yan L, Miao ZH, et al. Resveratrol inhibits oligomeric Aβ-induced microglial activation via NADPH oxidase. Mol Med Rep. 2015 Aug;12(4):6133-9. https://doi.org/10.3892/mmr.2015.4199
• 9 Gupta R, Gupta LK, Mediratta PK, Bhattacharya SK. Effect of resveratrol on scopolamine-induced cognitive impairment in mice. Pharmacol Rep. 2012 Mar/Apr;64(2):438-44. https://doi.org/10.1016/s1734-1140(12)70785-5
• 10 Deng H, Mi M. Resveratrol Attenuates Aβ25-35 Caused Neurotoxicity by Inducing Autophagy Through the TyrRS-PARP1-SIRT1 Signaling Pathway. Neurochem Res. 2016 May;41(9):2367-79. https://doi.org/10.1007/s11064-016-1950-9
• 11 Turner RS, Thomas RG, Craft S, van Dyck CH, Mintzer J, Reynolds BA, et al. A randomized, double-blind, placebo-controlled trial of resveratrol for Alzheimer disease. Neurology. 2015 Oct;85(16):1383-91. https://doi.org/10.1212/WNL.20200010202000102035
• 12 Ge JF, Qiao JP, Qi CC, Wang CW, Zhou JN. The binding of resveratrol to monomer and fibril amyloid beta. Neurochem Int. 2012 Dec;61(7):1192-201. https://doi.org/10.1016/j.neuint.2012.08.012
• 13 Wang J, Bi W, Cheng A, Freire D, Vempati P, Zhao W, et al. Targeting multiple pathogenic mechanisms with polyphenols for the treatment of Alzheimer’s disease-experimental approach and therapeutic implications. Front Aging Neurosci. 2014 Mar;6(42). https://doi.org/10.3389/fnagi.2014.00042
• 14 Chan S, Kantham S, M Rao V, Kumar Palanivelu M, L Pham H. Metal chelation, radical scavenging and inhibition of Aβ42 fibrillation by food constituents in relation to Alzheimer’s disease. Food Chem. 2016 May;199:185-94. https://doi.org/10.1016/j.foodchem.2015.11.118
• 15 Rege S, Geetha T, Broderick T, Babu J. Resveratrol protects β amyloid-induced oxidative damage and memory associated proteins in H19-7 hippocampal neuronal cells. Curr Alzheimer Res. 2015;12(2):147-56. https://doi.org/10.2174/1567205012666150204130009
• 16 Vingtdeux V, Giliberto L, Zhao H, Chandakkar P, Wu Q, Simon JE, et al. AMP-activated protein kinase signaling activation by resveratrol modulates amyloid-β peptide metabolism. J Biol Chem 2010 Mar;285(12):9100-13. https://doi.org/10.1074/jbc.M109.060061
• 17 Wen H, Fu Z, Wei Y, Zhang X, Ma L, Gu L, et al. Antioxidant Activity and Neuroprotective Activity of Stilbenoids in Rat Primary Cortex Neurons via the PI3K/Akt Signalling Pathway. Molecules. 2018 Sep;23(9):2328. https://doi.org/10.3390/molecules23092328
• 18 Corpas R, Griñán-Ferré C, Rodríguez-Farré E, Pallàs M, Sanfeliu C. Resveratrol Induces Brain Resilience Against Alzheimer Neurodegeneration Through Proteostasis Enhancement. Mol Neurobiol. 2018 Jun;56(2):1502-16. https://doi.org/10.1007/s12035-018-1157-y
• 19 Wang G, Chen L, Pan X, Chen J, Wang L, Wang W, et al. The effect of resveratrol on beta amyloid-induced memory impairment involves inhibition of phosphodiesterase-4 related signaling. Oncotarget. 2016 Mar;7(14);17380-92. https://doi.org/10.18632/oncotarget.8041
• 20 Solberg NO, Chamberlin R, Vigil JR, Deck LM, Heidrich JE, Brown DC, et al. Optical and SPION-enhanced MR imaging shows that trans-stilbene inhibitors of NF-κB concomitantly lower Alzheimer’s Disease plaque formation and microglial activation in AβPP/PS-1 transgenic mouse brain. J Alzheimers Dis. 2014 Mar;40(1):191-212. https://doi.org/10.3233/JAD-131031
• 21 Tafoya MA, Madi S, Sillerud LO. Superparamagnetic nanoparticle-enhanced MRI of Alzheimer’s disease plaques and activated microglia in 3X transgenic mouse brains: Contrast optimization: Optimizing MRI of 3X Tg AD Mouse Brains. J Magn Reson Imaging. 2017 Aug;46(2):574-88. https://doi.org/10.1002/jmri.25563
• 22 Frozza RL, Bernardi A, Hoppe JB, Meneghetti AB, Matté A, Battastini AM, et al. Neuroprotective effects of resveratrol against Aβ administration in rats are improved by lipid-core nanocapsules. Mol Neurobiol. 2013 Jan;47(3):1066-80. https://doi.org/10.1007/s12035-013-8401-2
• 23 Vion E, Page G, Bourdeaud E, Paccalin M, Guillard J, Rioux Bilan A. Trans ε-viniferin is an amyloid-β disaggregating and anti-inflammatory drug in a mouse primary cellular model of Alzheimer’s disease. Mol Cell Neurosci. 2018 Apr;88:1-6. https://doi.org/10.1016/j.mcn.2017.12.003
• 24 He X, Li Z, Rizak JD, Wu S, Wang Z, He R, et al. Resveratrol attenuates formaldehyde induced hyperphosphorylation of tau protein and cytotoxicity in N2a cells. Front Neurosci. 2017 Jan;31(10):598. https://doi.org/10.3389/fnins.2016.00598
• 25 Loureiro JA, Andrade S, Duarte A, Neves A, Queiroz J, Nunes C, et al. Resveratrol and grape extract-loaded solid lipid nanoparticles for the treatment of Alzheimer’s disease. Molecules. 2017 Feb;22(2):277. https://doi.org/10.3390/molecules22020277
• 26 Feng Y, Wang X, Yang S, Wang Y, Zhang X, Du X, et al. Resveratrol inhibits beta-amyloid oligomeric cytotoxicity but does not prevent oligomer formation. Neurotoxicology. 2009 Nov;30(6):986-95. https://doi.org/10.1016/j.neuro.2009.08.013
• 27 Ladiwala ARA, Lin JC, Bale SS, Marcelino-Cruz AM, Bhattacharya M, Dordick JS, et al. Resveratrol Selectively Remodels Soluble Oligomers and Fibrils of Amyloid Aβ into Off-pathway Conformers. J Biol Chem. 2010 Jul;285(31):24228-37. https://doi.org/10.1074/jbc.M110.133108
• 28 Rushworth JV, Griffiths HH, Watt NT, Hooper NM. Prion protein-mediated toxicity of amyloid-β oligomers requires lipid rafts and the transmembrane LRP1. J Biol Chem. 2013 Mar;288(13):8935-51. https://doi.org/10.1074/jbc.M112.400358
• 29 Fu Z, Aucoin D, Ahmed M, Ziliox M, Van Nostrand WE, Smith SO. Capping of Aβ42 Oligomers by Small Molecule Inhibitors. Biochemistry. 2014 Nov;53(50):7893-903. https://doi.org/10.1021/bi500910b
• 30 Hung VWS, Cheng XR, Li N, Veloso AJ, Kerman K. Electrochemical Detection of Amyloid-Beta Aggregation in the Presence of Resveratrol. J Electrochem Soc. 2013 Apr;160(7):G3097-101. https://doi.org/10.1149/2.014307jes
• 31 Regitz C, Fitzenberger E, Mahn FL, Dußling LM, Wenzel U. Resveratrol reduces amyloid-beta (Aβ1-42)-induced paralysis through targeting proteostasis in an Alzheimer model of Caenorhabditis elegans. Eur J Nutr. 2016 Apr;55(2):741-7. https://doi.org/10.1007/s00394-015-0894-1
• 32 Sathya M, Moorthi P, Premkumar P, Kandasamy M, Jayachandran KS, Anusuyadevi M. Resveratrol Intervenes Cholesterol- and Isoprenoid-Mediated Amyloidogenic Processing of AβPP in Familial Alzheimer’s Disease. J Alzheimers Dis. 2017 Sep;60(s1):S3-23. https://doi.org/10.3233/JAD-161034
• 33 Karuppagounder SS, Pinto JT, Xu H, Chen H-L, Beal MF, Gibson GE. Dietary supplementation with resveratrol reduces plaque pathology in a transgenic model of Alzheimer’s disease. Neurochem Int. 2009 Feb;54(2):111-8. https://doi.org/10.1016/j.neuint.2008.10.008
• 34 Varamini B, Sikalidis AK, Bradford KL. Resveratrol increases cerebral glycogen synthase kinase phosphorylation as well as protein levels of drebrin and transthyretin in mice: an exploratory study. Int J Food Sci Nutr. 2014;65(1):89-96. https://doi.org/10.3109/09637486.2013.832171
• 35 Santos LM, Rodrigues D, Alemi M, Silva SC, Ribeiro CA, Cardoso I. Resveratrol administration increases transthyretin protein levels, ameliorating AD features: the importance of transthyretin tetrameric stability. Mol Med. 2016 Jun;22(1):597-607. https://doi.org/10.2119/molmed.2016.00124
• 36 Zaky A, Mohammad B, Moftah M, Kandeel KM, Bassiouny AR. Apurinic/apyrimidinic endonuclease 1 is a key modulator of aluminum-induced neuroinflammation. BMC Neurosci. 2013 Mar;14(1):26. https://doi.org/10.1186/1471-2202-14-26
• 37 Haifeng Z, Qian W, Xuejiao C, Xuemin L, Na L. Inhibitive effect of resveratrol on the inflammation in cultured astrocytes and microglia induced by Aβ1-42. Neuroscience 2018 May;379:390-404. https://doi.org/10.1016/j.neuroscience.2018.03.047
• 38 Capiralla H, Vingtdeux V, Zhao H, Sankowski R, Al-Abed Y, Davies P, et al. Resveratrol mitigates lipopolysaccharide- and Aβ-mediated microglial inflammation by inhibiting the TLR4/NF-κB/STAT signaling cascade. J Neurochem. 2012 Feb;120(3):461-72. https://doi.org/10.1111/j.1471-4159.2011.07594.x
• 39 Huang TC, Lu KT, Wo YYP, Wu YJ, Yang YL. Resveratrol Protects Rats from Aβ-induced Neurotoxicity by the Reduction of iNOS Expression and Lipid Peroxidation. Musaro A, organizador. PLoS One 2011;6(12):e29102. https://doi.org/10.1371/journal.pone.0029102
• 40 Colin J, Allouche A, Chauveau F, Corbier C, Pauron-Gregory L, Lanhers M-C, et al. Improved neuroprotection provided by drug combination in neurons exposed to cell-derived soluble amyloid-β peptide. J Alzheimers Dis. 2016 May;52(3):975-87. https://doi.org/10.3233/JAD-151110
• 41 Gong Q, Li F, Jin F, Chan N. Resveratrol Attenuates Neuroinflammation-mediated Cognitive Deficits in Rats. J Health Sci. 2010;56(6):655-63. https://doi.org/https://doi.org/10.1248/jhs.56.655
• 42 Manczak M, Mao P, Calkins MJ, Cornea A, Reddy AP, Murphy MP, et al. Mitochondria-targeted antioxidants protect against amyloid-β toxicity in Alzheimer’s disease neurons. J Alzheimer Dis. 2010 Jun;20(s2):S609-31. https://doi.org/10.3233/JAD-2010-100564
• 43 Hui Y, Chengyong T, Cheng L, Haixia H, Yuanda Z, Weihua Y. Resveratrol attenuates the cytotoxicity induced by amyloid-β1-42 in PC12 cells by upregulating heme oxygenase-1 via the PI3K/Akt/Nrf2 pathway. Neurochem Res. 2018 Oct;43(2):297-305. https://doi.org/10.1007/s11064-017-2421-7
• 44 Ko SY, Ko HA, Chu KH, Shieh TM, Chi TC, Chen HI, et al. The possible mechanism of advanced glycation end products (AGEs) for Alzheimer’s disease. PLoS One. 2015 Nov;10(11):e0143345. https://doi.org/10.1371/journal.pone.0143345
• 45 Zhao HF, Li N, Wang Q, Cheng XJ, Li XM, Liu TT. Resveratrol decreases the insoluble Aβ1-42 level in hippocampus and protects the integrity of the blood-brain barrier in AD rats. Neuroscience. 2015 Dec;310:641-9. https://doi.org/10.1016/j.neuroscience.2015.10.006
• 46 Moussa C, Hebron M, Huang X, Ahn J, Rissman RA, Aisen PS, et al. Resveratrol regulates neuro-inflammation and induces adaptive immunity in Alzheimer’s disease. J Neuroinflammation. 2017 Jan;14(1):1. https://doi.org/10.1186/s12974-016-0779-0
• 47 Albani D, Polito L, Batelli S, De Mauro S, Fracasso C, Martelli G, et al. The SIRT1 activator resveratrol protects SK-N-BE cells from oxidative stress and against toxicity caused by α-synuclein or amyloid-β (1-42) peptide. J Neurochem. 2009 Sep;110(5):1445-56. https://doi.org/10.1111/j.1471-4159.2009.06228.x
• 48 Porquet D, Casadesús G, Bayod S, Vicente A, Canudas AM, Vilaplana J, et al. Dietary resveratrol prevents Alzheimer’s markers and increases life span in SAMP8. AGE. 2013 Nov;35(5):1851-65. https://doi.org/10.1007/s11357-012-9489-4
• 49 Scuderi C, Stecca C, Bronzuoli MR, Rotili D, Valente S, Mai A, et al. Sirtuin modulators control reactive gliosis in an in vitro model of Alzheimer's disease. Front Pharmacol. 2014 May;13(5)89. https://doi.org/10.3389/fphar.2014.00089
• 50 Wang R, Zhang Y, Li J, Zhang C. Resveratrol ameliorates spatial learning memory impairment induced by Aβ 1-42 in rats. Neuroscience. 2017 Mar;344:39-47. https://doi.org/10.1016/j.neuroscience.2016.08.051
• 51 Porquet D, Griñán-Ferré C, Ferrer I, Camins A, Sanfeliu C, del Valle J, et al. Neuroprotective Role of Trans-Resveratrol in a Murine Model of Familial Alzheimer’s Disease. J Alzheimers Dis. 2014;42(4):1209-20. https://doi.org/10.3233/JAD-140444
• 52 El-Sayed NS, Bayan Y. Possible role of resveratrol targeting estradiol and neprilysin pathways in lipopolysaccharide model of Alzheimer disease. Adv Exp Med Biol. 2015 Oct;822:107-18. https://doi.org/10.1007/978-3-319-08927-0_12
• 53 Wang H, Jiang T, Li W, Gao N, Zhang T. Resveratrol attenuates oxidative damage through activating mitophagy in an in vitro model of Alzheimer’s disease. Toxicol Lett. 2018 Jan;282:100-8. https://doi.org/10.1016/j.toxlet.2017.10.021
• 54 Yang L, Wang W, Chen J, Wang N, Zheng G. A comparative study of resveratrol and resveratrol-functional selenium nanoparticles: Inhibiting amyloid β aggregation and reactive oxygen species formation properties. J Biomed Mater Res A. 2018 Dec;106(12):3034-41. https://doi.org/10.1002/jbm.a.36493
• 55 Yin H, Wang H, Zhang H, Gao N, Zhang T, Yang Z. Resveratrol attenuates Aβ-induced early hippocampal neuron excitability impairment via recovery of function of potassium channels. Neurotox Res. 2017 Oct;32(3):311-24. https://doi.org/10.1007/s12640-017-9726-9
• 56 Reddy PH, Manczak M, Yin X, Grady MC, Mitchell A, Kandimalla R, et al. Protective effects of a natural product, curcumin, against amyloid β induced mitochondrial and synaptic toxicities in Alzheimer’s disease. J Investig Med. 2016;64(8):1220-34. https://doi.org/10.1136/jim-2016-000240
• 57 Sun J, Zhang X, Wang C, Teng Z, Li Y. Curcumin decreases hyperphosphorylation of tau by down-regulating caveolin-1/GSK-3β in N2a/APP695swe cells and APP/PS1 double transgenic Alzheimer’s disease mice. Am J Chin Med. 2017 Nov;45(8):1667-82. https://doi.org/10.1142/S0192415X17500902
• 58 Sundaram JR, Poore CP, Sulaimee NHB, Pareek T, Cheong WF, Wenk MR, et al. Curcumin ameliorates neuroinflammation, neurodegeneration, and memory deficits in p25 transgenic mouse model that bears hallmarks of Alzheimer’s disease. J Alzheimers Dis. 2017 Nov;60(4):1429-42. https://doi.org/10.3233/JAD-170093
• 59 Chang X, Rong C, Chen Y, Yang C, Hu Q, Mo Y, et al. (−)-Epigallocatechin-3-gallate attenuates cognitive deterioration in Alzheimer’s disease model mice by upregulating neprilysin expression. Exp Cell Res. 2015 May;334(1):136-45. https://doi.org/10.1016/j.yexcr.2015.04.004
• 60 Zhang ZX, Li YB, Zhao RP. Epigallocatechin gallate attenuates β-amyloid generation and oxidative stress involvement of PPARγ in N2a/APP695 cells. Neurochem Res. 2017 Feb;42(2):468-80. https://doi.org/10.1007/s11064-016-2093-8
• 61 Cheng-Chung Wei J, Huang HC, Chen WJ, Huang CN, Peng CH, Lin CL. Epigallocatechin gallate attenuates amyloid β-induced inflammation and neurotoxicity in EOC 13.31 microglia. Eur J Pharmacol. 2016 Jan;770:16-24. https://doi.org/10.1016/j.ejphar.2015.11.048
• 62 Guo Y, Zhao Y, Nan Y, Wang X, Chen Y, Wang S. (−)-Epigallocatechin-3-gallate ameliorates memory impairment and rescues the abnormal synaptic protein levels in the frontal cortex and hippocampus in a mouse model of Alzheimer’s disease. Neuroreport. 2017 Jul;28(10):590-7. https://doi.org/10.1097/WNR.20200010202000100803
• 63 Wang J, Varghese M, Ono K, Yamada M, Levine S, Tzavaras N, et al. Cocoa Extracts Reduce Oligomerization of Amyloid-β: Implications for Cognitive Improvement in Alzheimer’s Disease. J Alzheimers Dis. 2014 Jun;41(2):643-50. https://doi.org/10.3233/JAD-132231
• 64 Cimini A, Gentile R, D’Angelo B, Benedetti E, Cristiano L, Avantaggiati ML, et al. Cocoa powder triggers neuroprotective and preventive effects in a human Alzheimer’s disease model by modulating BDNF signaling pathway: cocoa for Alzheimer’s disease protection. J Cell Biochem. 2013 Mar;114(10):2209-20. https://doi.org/10.1002/jcb.24548