Resveratrol Rescues Tau-Induced Cognitive Deficits and Neuropathology in a Mouse Model of Tauopathy

Author(s): Xiao-Ying Sun, Quan-Xiu Dong, Jie Zhu, Xun Sun, Li-Fan Zhang, Mandy Qiu, Xiao-Lin Yu*, Rui-Tian Liu*.

Journal Name: Current Alzheimer Research

Volume 16 , Issue 8 , 2019

  Journal Home
Translate in Chinese
Become EABM
Become Reviewer

Abstract:

Background: Alzheimer’s Disease (AD) is characterized by the presence of extracellular amyloid-β (Aβ) plaques and intraneuronal neurofibrillary tangles assembled by the microtubuleassociated protein tau. Increasing evidence demonstrated that tau pathology played an important role in AD progression. Resveratrol (RSV) has previously proved to exert neuroprotective effect against AD by inhibiting Aβ generation and Aβ-induced neurocytotoxicity, while its effect on tau pathology is still unknown.

Methods: The effect of RSV on tau aggregation was measured by Thioflavin T fluorescence and Transmission electron microscope imaging. The effect of RSV on tau oligomer-induced cytotoxicity was assessed by MTT assay and the uptake of extracellular tau by N2a cells was determined by immunocytochemistry. 6-month-old male PS19 mice were treated with RSV or vehicle by oral administration (gavage) once a day for 5 weeks. The cognitive performance was determined using Morris water maze test, object recognition test and Y-maze test. The levels of phosphorylated-tau, gliosis, proinflammatory cytokines such as TNF-α and IL-1β, and synaptic proteins including synaptophysin and PSD95 in the brains of the mice were evaluated by immunoblotting, immunostaining and ELISA, respectively.

Results: RSV significantly inhibited tau aggregation and tau oligomer-induced cytotoxicity, and blocked the uptake of extracellular tau oligomers by N2a cells. When applied to PS19 mice, RSV treatment effectively rescued cognitive deficits, reducing the levels of phosphorylated tau, neuroinflammation and synapse loss in the brains of mice.

Conclusion: These findings suggest that RSV has promising therapeutic potential for AD and other tauopathies.

Keywords: Resveratrol, Alzheimer's disease, tau, oligomer, neuroinflammation, synapse loss.

[1]
Blennow K, de Leon MJ, Zetterberg H. Alzheimer’s disease. Lancet 368(9533): 387-403. 2006
[http://dx.doi.org/10.1016/S0140-6736(06)69113-7] [PMID: 16876668]
[2]
Graham WV, Bonito-Oliva A, Sakmar TP. Update on Alzheimer’s Disease Therapy and Prevention Strategies. Annu Rev Med 68: 413-30. 2017
[http://dx.doi.org/10.1146/annurev-med-042915-103753] [PMID: 28099083]
[3]
Congdon EE, Sigurdsson EM. Tau-targeting therapies for Alzheimer disease. Nat Rev Neurol 14(7): 399-415. 2018
[http://dx.doi.org/10.1038/s41582-018-0013-z] [PMID: 29895964]
[4]
Wang Y, Mandelkow E. Tau in physiology and pathology. Nat Rev Neurosci 17(1): 5-21. 2016
[http://dx.doi.org/10.1038/nrn.2015.1] [PMID: 26631930]
[5]
Vershinin M, Carter BC, Razafsky DS, King SJ, Gross SP. Multiple-motor based transport and its regulation by Tau. Proc Natl Acad Sci USA 104(1): 87-92. 2007
[http://dx.doi.org/10.1073/pnas.0607919104] [PMID: 17190808]
[6]
Dixit R, Ross JL, Goldman YE, Holzbaur EL. Differential regulation of dynein and kinesin motor proteins by tau. Science 319(5866): 1086-9. 2008
[http://dx.doi.org/10.1126/science.1152993] [PMID: 18202255]
[7]
Spires-Jones TL, Stoothoff WH, de Calignon A, Jones PB, Hyman BT. Tau pathophysiology in neurodegeneration: a tangled issue. Trends Neurosci 32(3): 150-9. 2009
[http://dx.doi.org/10.1016/j.tins.2008.11.007] [PMID: 19162340]
[8]
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 USA 83(13): 4913-7. 1986
[http://dx.doi.org/10.1073/pnas.83.13.4913] [PMID: 3088567]
[9]
Min SW, Chen X, Tracy TE, Li Y, Zhou Y, Wang C, et al. Critical role of acetylation in tau-mediated neurodegeneration and cognitive deficits. Nat Med 21(10): 1154-62. 2015
[http://dx.doi.org/10.1038/nm.3951] [PMID: 26390242]
[10]
Wang JZ, Grundke-Iqbal I, Iqbal K. Glycosylation of microtubule-associated protein tau: an abnormal posttranslational modification in Alzheimer’s disease. Nat Med 2(8): 871-5. 1996
[http://dx.doi.org/10.1038/nm0896-871] [PMID: 8705855]
[11]
Mena R, Edwards PC, Harrington CR, Mukaetova-Ladinska EB, Wischik CM. Staging the pathological assembly of truncated tau protein into paired helical filaments in Alzheimer’s disease. Acta Neuropathol 91(6): 633-41. 1996
[http://dx.doi.org/10.1007/s004010050477] [PMID: 8781663]
[12]
Ittner A, Ittner LM. Dendritic tau in Alzheimer’s disease. Neuron 99(1): 13-27. 2018
[http://dx.doi.org/10.1016/j.neuron.2018.06.003] [PMID: 30001506]
[13]
Li C, Götz J. Tau-based therapies in neurodegeneration: opportunities and challenges. Nat Rev Drug Discov 16(12): 863-83. 2017
[http://dx.doi.org/10.1038/nrd.2017.155] [PMID: 28983098]
[14]
Novak P, Kontsekova E, Zilka N, Novak M. Ten years of tau-targeted immunotherapy: the path walked and the roads ahead. Front Neurosci 12: 798. 2018
[http://dx.doi.org/10.3389/fnins.2018.00798] [PMID: 30450030]
[15]
Sigurdsson EM. Tau immunotherapies for Alzheimer’s disease and related tauopathies: progress and potential pitfalls. J Alzheimers Dis 64(s1): S555-65. 2018
[http://dx.doi.org/10.3233/JAD-179937] [PMID: 29865056]
[16]
Sawda C, Moussa C, Turner RS. Resveratrol for Alzheimer’s disease. Ann N Y Acad Sci 2017. 1403(1): 142-9.
[http://dx.doi.org/10.1111/nyas.13431] [PMID: 28815614]
[17]
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 14(1): 1. 2017
[http://dx.doi.org/10.1186/s12974-016-0779-0] [PMID: 28086917]
[18]
Feng Y, Wang XP, Yang SG, Wang YJ, Zhang X, Du XT, et al. Resveratrol inhibits beta-amyloid oligomeric cytotoxicity but does not prevent oligomer formation. Neurotoxicology 30(6): 986-95. 2009
[http://dx.doi.org/10.1016/j.neuro.2009.08.013] [PMID: 19744518]
[19]
Rege SD, Geetha T, Griffin GD, Broderick TL, Babu JR. Neuroprotective effects of resveratrol in Alzheimer disease pathology. Front Aging Neurosci 6: 218. 2014
[http://dx.doi.org/10.3389/fnagi.2014.00218] [PMID: 25309423]
[20]
Zhang LF, Yu XL, Ji M, Liu SY, Wu XL, Wang YJ, et al. Resveratrol alleviates motor and cognitive deficits and neuropathology in the A53T α-synuclein mouse model of Parkinson’s disease. Food Funct 9(12): 6414-26. 2018
[http://dx.doi.org/10.1039/C8FO00964C] [PMID: 30462117]
[21]
Anandhan A, Tamilselvam K, Vijayraja D, Ashokkumar N, Rajasankar S, Manivasagam T. Resveratrol attenuates oxidative stress and improves behaviour in 1 -methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) challenged mice. Ann Neurosci 17(3): 113-9. 2010
[http://dx.doi.org/10.5214/ans.0972-7531.1017304] [PMID: 25205886]
[22]
Pasinetti GM, Wang J, Marambaud P, Ferruzzi M, Gregor P, Knable LA, et al. Neuroprotective and metabolic effects of resveratrol: therapeutic implications for Huntington’s disease and other neurodegenerative disorders. Exp Neurol 232(1): 1-6. 2011
[http://dx.doi.org/10.1016/j.expneurol.2011.08.014] [PMID: 21907197]
[23]
Naia L, Rosenstock TR, Oliveira AM, Oliveira-Sousa SI, Caldeira GL, Carmo C, et al. Comparative mitochondrial-based protective effects of resveratrol and nicotinamide in Huntington’s disease models. Mol Neurobiol 54(7): 5385-99. 2017
[http://dx.doi.org/10.1007/s12035-016-0048-3] [PMID: 27590140]
[24]
Song L, Chen L, Zhang X, Li J, Le W. Resveratrol ameliorates motor neuron degeneration and improves survival in SOD1(G93A) mouse model of amyotrophic lateral sclerosis. BioMed Res Int 2014483501 2014
[http://dx.doi.org/10.1155/2014/483501] [PMID: 25057490]
[25]
Tellone E, Galtieri A, Russo A, Giardina B, Ficarra S. Resveratrol: a focus on several neurodegenerative diseases. Oxid Med Cell Longev 2015392169 2015
[http://dx.doi.org/10.1155/2015/392169] [PMID: 26180587]
[26]
Drygalski K, Fereniec E, Koryciński K, Chomentowski A, Kiełczewska A, Odrzygóźdź C, et al. Resveratrol and Alzheimer’s disease. From molecular pathophysiology to clinical trials. Exp Gerontol 113: 36-47. 2018
[http://dx.doi.org/10.1016/j.exger.2018.09.019] [PMID: 30266470]
[27]
Jhang KA, Park JS, Kim HS, Chong YH. Resveratrol ameliorates tau hyperphosphorylation at ser396 site and oxidative damage in rat hippocampal slices exposed to vanadate: implication of erk1/2 and gsk-3β signaling cascades. J Agric Food Chem 65(44): 9626-34. 2017
[http://dx.doi.org/10.1021/acs.jafc.7b03252] [PMID: 29022339]
[28]
Schweiger S, Matthes F, Posey K, Kickstein E, Weber S, Hettich MM, et al. Resveratrol induces dephosphorylation of Tau by interfering with the MID1-PP2A complex. Sci Rep 7(1): 13753. 2017
[http://dx.doi.org/10.1038/s41598-017-12974-4] [PMID: 29062069]
[29]
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 10: 598. 2017
[http://dx.doi.org/10.3389/fnins.2016.00598] [PMID: 28197064]
[30]
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 85(16): 1383-91. 2015
[http://dx.doi.org/10.1212/WNL.0000000000002035] [PMID: 26362286]
[31]
Yoshiyama Y, Higuchi M, Zhang B, Huang SM, Iwata N, Saido TC, et al. Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron 53(3): 337-51. 2007
[http://dx.doi.org/10.1016/j.neuron.2007.01.010] [PMID: 17270732]
[32]
Li W, Lee VM. Characterization of two VQIXXK motifs for tau fibrillization in vitro. Biochemistry 45(51): 15692-701. 2006
[http://dx.doi.org/10.1021/bi061422+] [PMID: 17176091]
[33]
Berger Z, Roder H, Hanna A, Carlson A, Rangachari V, Yue M, et al. Accumulation of pathological tau species and memory loss in a conditional model of tauopathy. J Neurosci 27(14): 3650-62. 2007
[http://dx.doi.org/10.1523/JNEUROSCI.0587-07.2007] [PMID: 17409229]
[34]
Kinney JW, Bemiller SM, Murtishaw AS, Leisgang AM, Salazar AM, Lamb BT. Inflammation as a central mechanism in Alzheimer’s disease. Alzheimers Dement (N Y) 4: 575-90. 2018
[http://dx.doi.org/10.1016/j.trci.2018.06.014] [PMID: 30406177]
[35]
Tracy TE, Gan L. Tau-mediated synaptic and neuronal dysfunction in neurodegenerative disease. Curr Opin Neurobiol 51: 134-8. 2018
[http://dx.doi.org/10.1016/j.conb.2018.04.027] [PMID: 29753269]
[36]
Zhu X, Wu C, Qiu S, Yuan X, Li L. Effects of resveratrol on glucose control and insulin sensitivity in subjects with type 2 diabetes: systematic review and meta-analysis. Nutr Metab (Lond) 14: 60. 2017
[http://dx.doi.org/10.1186/s12986-017-0217-z] [PMID: 29018489]
[37]
Zordoky BN, Robertson IM, Dyck JR. Preclinical and clinical evidence for the role of resveratrol in the treatment of cardiovascular diseases. Biochim Biophys Acta 1852(6): 1155-77. 2015
[http://dx.doi.org/10.1016/j.bbadis.2014.10.016] [PMID: 25451966]
[38]
Nelson PT, Jicha GA, Schmitt FA, Liu H, Davis DG, Mendiondo MS, et al. Clinicopathologic correlations in a large Alzheimer disease center autopsy cohort: neuritic plaques and neurofibrillary tangles “do count” when staging disease severity. J Neuropathol Exp Neurol 66(12): 1136-46. 2007
[http://dx.doi.org/10.1097/nen.0b013e31815c5efb] [PMID: 18090922]
[39]
Lee SH, Le Pichon CE, Adolfsson O, Gafner V, Pihlgren M, Lin H, et al. Antibody-mediated targeting of tau In vivo does not require effector function and microglial engagement. Cell Rep 16(6): 1690-700. 2016
[http://dx.doi.org/10.1016/j.celrep.2016.06.099] [PMID: 27475227]
[40]
de la Monte SM. Insulin resistance and neurodegeneration: progress towards the development of new therapeutics for Alzheimer’s disease. Drugs 77(1): 47-65. 2017
[http://dx.doi.org/10.1007/s40265-016-0674-0] [PMID: 27988872]
[41]
Llorens-Martín M, Jurado J, Hernández F, Avila J. GSK-3β, a pivotal kinase in Alzheimer disease. Front Mol Neurosci 7: 46. 2014
[PMID: 24904272]
[42]
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 (Dordr) 35(5): 1851-65. 2013
[http://dx.doi.org/10.1007/s11357-012-9489-4] [PMID: 23129026]
[43]
Lindwall G, Cole RD. Phosphorylation affects the ability of tau protein to promote microtubule assembly. J Biol Chem 259(8): 5301-5. 1984
[PMID: 6425287]
[44]
Kidd M. Paired helical filaments in electron microscopy of Alzheimer’s disease. Nature 197: 192-3. 1963
[http://dx.doi.org/10.1038/197192b0] [PMID: 14032480]
[45]
Meraz-Ríos MA, Lira-De León KI, Campos-Peña V, De Anda-Hernández MA, Mena-López R. Tau oligomers and aggregation in Alzheimer’s disease. J Neurochem 112(6): 1353-67. 2010
[http://dx.doi.org/10.1111/j.1471-4159.2009.06511.x] [PMID: 19943854]
[46]
Shafiei SS, Guerrero-Muñoz MJ, Castillo-Carranza DL. Tau oligomers: cytotoxicity, propagation, and mitochondrial damage. Front Aging Neurosci 9: 83. 2017
[http://dx.doi.org/10.3389/fnagi.2017.00083] [PMID: 28420982]
[47]
Cárdenas-Aguayo Mdel C, Gómez-Virgilio L, DeRosa S, Meraz-Ríos MA. The role of tau oligomers in the onset of Alzheimer’s disease neuropathology. ACS Chem Neurosci 5(12): 1178-91. 2014
[http://dx.doi.org/10.1021/cn500148z] [PMID: 25268947]
[48]
Lasagna-Reeves CA, Sengupta U, Castillo-Carranza D, Gerson JE, Guerrero-Munoz M, Troncoso JC, et al. The formation of tau pore-like structures is prevalent and cell specific: possible implications for the disease phenotypes. Acta Neuropathol Commun 2: 56. 2014
[http://dx.doi.org/10.1186/2051-5960-2-56] [PMID: 24887264]
[49]
Heneka MT, Carson MJ, El Khoury J. Neuroinflammation in Alzheimer’s disease. Lancet Neurol 14(4): 388-405. 2015
[http://dx.doi.org/10.1016/S1474-4422(15)70016-5] [PMID: 25792098]
[50]
Hansen DV, Hanson JE, Sheng M. Microglia in Alzheimer’s disease. J Cell Biol 217(2): 459-72. 2018
[http://dx.doi.org/10.1083/jcb.201709069] [PMID: 29196460]
[51]
Renaud J, Martinoli MG. Resveratrol as a protective molecule for neuroinflammation: a review of mechanisms. Curr Pharm Biotechnol 15(4): 318-29. 2014
[http://dx.doi.org/10.2174/1389201015666140617101332] [PMID: 24938890]
[52]
Dejanovic B, Huntley MA, De Mazière A. Meilandt WJ4, Wu T4, Srinivasan K, et alChanges in the synaptic proteome in tauopathy and rescue of tau-induced synapse loss by C1q antibodies. Neuron 100(6): 1322-1336.e7. 2018
[http://dx.doi.org/10.1016/j.neuron.2018.10.014] [PMID: 30392797]
[53]
Bloom GS. Amyloid-β and tau: the trigger and bullet in Alzheimer disease pathogenesis. JAMA Neurol 71(4): 505-8. 2014
[http://dx.doi.org/10.1001/jamaneurol.2013.5847] [PMID: 24493463]
[54]
Clinton LK, Blurton-Jones M, Myczek K, Trojanowski JQ, LaFerla FM. Synergistic Interactions between Abeta, tau, and alpha-synuclein: acceleration of neuropathology and cognitive decline. J Neurosci 30(21): 7281-9. 2010
[http://dx.doi.org/10.1523/JNEUROSCI.0490-10.2010] [PMID: 20505094]


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 16
ISSUE: 8
Year: 2019
Page: [710 - 722]
Pages: 13
DOI: 10.2174/1567205016666190801153751
Price: $58

Article Metrics

PDF: 23
HTML: 1