Abstract
Alzheimer’s disease (AD), the most common type of dementia, is a devastating neurodegenerative disease characterized by progressive neuro-cognitive dysfunction. In our study, we investigated the potential of 3,4-dihydroxyphenylethanol (DOPET), a dopamine metabolite, and also a polyphenol from olive oil, in ameliorating soluble oligomeric amyloid β1–42 plus ibotenic acid (oA42i)-induced neuro-behavioral dysfunction in C57BL/6 mice. The results depicted that intracerebroventricular injection of oA42i negatively altered the spatial reference and working memories in mice, whereas DOPET treatment significantly augmented the spatio-cognitive abilities against oA42i. Upon investigation of the underlying mechanisms, oA42i-intoxicated mice displayed significantly activated death kinases including JNK- and p38-MAPKs with concomitantly inhibited ERK-MAPK/RSK2, PI3K/Akt1, and JAK2/STAT3 survival signaling pathways in the hippocampal neurons. Conversely, DOPET treatment reversed these dysregulated signaling mechanisms comparable to the sham-operated mice. Notably, oA42i administration altered the Bcl-2/Bad levels and activated the caspase-dependent mitochondria-mediated apoptotic pathway involving cytochrome c, apoptotic protease activating factor-1, and caspase-9/3. In contrary, DOPET administration stabilized the dysregulated activities of these apoptotic/anti-apoptotic markers and preserved the mitochondrial ultra-architecture. Besides, we observed that oA42i intoxication substantially down-regulated the expression of genes involved in the regulation of survival and memory functions including sirtuin-1, cyclic AMP response element-binding protein (CREB), CREB-target genes (BDNF, c-Fos, Nurr1, and Egr1) and a disintegrin and metalloprotease 10. Fascinatingly, DOPET treatment significantly diminished these aberrations when compared to the oA42i group. Taken together, these results accentuate that DOPET may be a multipotent agent to combat AD.
Similar content being viewed by others
References
Auñon-Calles D, Canut L, Visioli F (2013) Toxicological evaluation of pure hydroxytyrosol. Food Chem Toxicol 55:498–504
Bayram B, Ozcelik B, Grimm S, Roeder T, Schrader C, Ernst IM, Wagner AE, Grune T, Frank J, Rimbach G (2012) A diet rich in olive oil phenolics reduces oxidative stress in the heart of SAMP8 mice by induction of Nrf2-dependent gene expression. Rejuvenation Res 15:71–81
Benilova I, Karran E, De Strooper B (2012) The toxic Aβ oligomer and Alzheimer’s disease: an emperor in need of clothes. Nat Neurosci 15:349–357
Brown RW, Beale KS, Jay Frye GD (2002) Mecamylamine blocks enhancement of reference memory but not working memory produced by post-training injection of nicotine in rats tested on the radial arm maze. Behav Brain Res 134:259–265
Cao K, Xu J, Zou X, Li Y, Chen C, Zheng A, Li H, Li H, Szeto IM, Shi Y, Long J, Liu J, Feng Z (2014) Hydroxytyrosol prevents diet-induced metabolic syndrome and attenuates mitochondrial abnormalities in obese mice. Free Radic Biol Med 67:396–407
Capasso G, Di Gennaro CI, Della Ragione F, Manna C, Ciarcia R, Florio S, Perna A, Pollastro RM, Damiano S, Mazzoni O, Galletti P, Zappia V (2008) In vivo effect of the natural antioxidant hydroxytyrosol on cyclosporine nephrotoxicity in rats. Nephrol Dial Transplant 23:1186–1195
Chiba T, Yamada M, Sasabe J, Terashita K, Shimoda M, Matsuoka M, Aiso S (2009) Amyloid-beta causes memory impairment by disturbing the JAK2/STAT3 axis in hippocampal neurons. Mol Psychiatry 14:206–222
Daccache A, Lion C, Sibille N, Gerard M, Slomianny C, Lippens G, Cotelle P (2011) Oleuropein and derivatives from olives as Tau aggregation inhibitors. Neurochem Int 58:700–707
de la Puerta R, Ruiz Gutierrez V, Hoult JR (1999) Inhibition of leukocyte 5-lipoxygenase by phenolics from virgin olive oil. Biochem Pharmacol 57:445–449
de la Torre R, Covas MI, Pujadas MA, Fitó M, Farré M (2006) Is dopamine behind the health benefits of red wine? Eur J Nutr 45:307–310
Denner LA, Rodriguez-Rivera J, Haidacher SJ, Jahrling JB, Carmical JR, Hernandez CM, Zhao Y, Sadygov RG, Starkey JM, Spratt H, Luxon BA, Wood TG, Dineley KT (2012) Cognitive enhancement with rosiglitazone links the hippocampal PPARγ and ERK MAPK signaling pathways. J Neurosci 32:16725–16735
Epis R, Marcello E, Gardoni F, Longhi A, Calvani M, Iannuccelli M, Cattabeni F, Canonico PL, Di Luca M (2008) Modulatory effect of acetyl-l-carnitine on amyloid precursor protein metabolism in hippocampal neurons. Eur J Pharmacol 597:51–56
España J, Valero J, Miñano-Molina AJ, Masgrau R, Martín E, Guardia-Laguarta C, Lleó A, Giménez-Llort L, Rodríguez-Alvarez J, Saura CA (2010) Beta-amyloid disrupts activity-dependent gene transcription required for memory through the CREB coactivator CRTC1. J Neurosci 30:9402–9410
Feng C, Zhang C, Shao X, Liu Q, Qian Y, Feng L, Chen J, Zha Y, Zhang Q, Jiang X (2012) Enhancement of nose-to-brain delivery of basic fibroblast growth factor for improving rat memory impairments induced by co-injection of β-amyloid and ibotenic acid into the bilateral hippocampus. Int J Pharm 423:226–234
Fiocchetti M, De Marinis E, Ascenzi P, Marino M (2013) Neuroglobin and neuronal cell survival. Biochim Biophys Acta 1834:1744–1749
Gao J, Wang WY, Mao YW, Gräff J, Guan JS, Pan L, Mak G, Kim D, Su SC, Tsai LH (2010) A novel pathway regulates memory and plasticity via SIRT1 and miR-134. Nature 466:1105–1109
Godoy JA, Rios JA, Zolezzi JM, Braidy N, Inestrosa NC (2014) Signaling pathway cross talk in Alzheimer’s disease. Cell Commun Signal 12:23
González-Correa JA, Navas MD, Lopez-Villodres JA, Trujillo M, Espartero JL, De La Cruz JP (2008) Neuroprotective effect of hydroxytyrosol and hydroxytyrosol acetate in rat brain slices subjected to hypoxia-reoxygenation. Neurosci Lett 446:143–146
González-Santiago M, Martín-Bautista E, Carrero JJ, Fonollá J, Baró L, Bartolomé MV, Gil-Loyzaga P, López-Huertas E (2006) One-month administration of hydroxytyrosol, phenolic antioxidant present in olive oil, to hyperlipemic rabbits improves blood lipid profile, antioxidant status and reduces atherosclerosis development. Atherosclerosis 188:35–42
Granados-Principal S, El-Azem N, Pamplona R, Ramirez-Tortosa C, Pulido-Moran M, Vera-Ramirez L, Quiles JL, Sanchez-Rovira P, Naudí A, Portero-Otin M, Perez-Lopez P, Ramirez-Tortosa M (2014) Hydroxytyrosol ameliorates oxidative stress and mitochondrial dysfunction in doxorubicin-induced cardiotoxicity in rats with breast cancer. Biochem Pharmacol 90:25–33
Gutiérrez-Lerma AI, Ordaz B, Peña-Ortega F (2013) Amyloid Beta peptides differentially affect hippocampal theta rhythms in vitro. Int J Pept 2013:328140
Hagiwara K, Goto T, Araki M, Miyazaki H, Hagiwara H (2011) Olive polyphenol hydroxytyrosol prevents bone loss. Eur J Pharmacol 662:78–84
Hajibagheri MAN (1999) Methods in molecular biology: electron microscopy methods and protocols, vol 117. Humana Press, Totowa
He N, Jin WL, Lok KH, Wang Y, Yin M, Wang ZJ (2013) Amyloid-β(1-42) oligomer accelerates senescence in adult hippocampal neural stem/progenitor cells via formylpeptide receptor 2. Cell Death Dis 4:e924
Hruska Z, Dohanich GP (2007) The effects of chronic estradiol treatment on working memory deficits induced by combined infusion of beta-amyloid (1–42) and ibotenic acid. Horm Behav 52:297–306
Hu Y, Xia Z, Sun Q, Orsi A, Rees D (2005) A new approach to the pharmacological regulation of memory: Sarsasapogenin improves memory by elevating the low muscarinic acetylcholine receptor density in brains of memory-deficit rat models. Brain Res 1060:26–39
Jin M, Shepardson N, Yang T, Chen G, Walsh D, Selkoe DJ (2011) Soluble amyloid beta-protein dimers isolated from Alzheimer cortex directly induce Tau hyperphosphorylation and neuritic degeneration. Proc Natl Acad Sci USA 108:5819–5824
Kawamata J, Shimohama S (2011) Stimulating nicotinic receptors trigger multiple pathways attenuating cytotoxicity in models of Alzheimer’s and Parkinson’s diseases. J Alzheimers Dis 24(Suppl 2):95–109
Kayed R, Lasagna-Reeves CA (2013) Molecular mechanisms of amyloid oligomers toxicity. J Alzheimers Dis 33(Suppl 1):S67–S78
Kim EK, Choi EJ (2010) Pathological roles of MAPK signaling pathways in human diseases. Biochim Biophys Acta 1802:396–405
Klein WL (2002) Abeta toxicity in Alzheimer’s disease: globular oligomers (ADDLs) as new vaccine and drug targets. Neurochem Int 41:345–352
Lee-Huang S, Huang PL, Zhang D, Lee JW, Bao J, Sun Y, Chang YT, Zhang J, Huang PL (2007) Discovery of small-molecule HIV-1 fusion and integrase inhibitors oleuropein and hydroxytyrosol: Part I. fusion (corrected) inhibition. Biochem Biophys Res Commun 354:872–878
Liao FF, Xu H (2009) Insulin signaling in sporadic Alzheimer’s disease. Sci Signal 2:pe36
Ma QL, Yang F, Rosario ER, Ubeda OJ, Beech W, Gant DJ, Chen PP, Hudspeth B, Chen C, Zhao Y, Vinters HV, Frautschy SA, Cole GM (2009) Beta-amyloid oligomers induce phosphorylation of tau and inactivation of insulin receptor substrate via c-Jun N-terminal kinase signaling: suppression by omega-3 fatty acids and curcumin. J Neurosci 29:9078–9089
Marwarha G, Ghribi O (2012) Leptin signaling and Alzheimer’s disease. Am J Neurodegener Dis 1:245–265
Morimoto K, Yoshimi K, Tonohiro T, Yamada N, Oda T, Kaneko I (1998) Co-injection of beta-amyloid with ibotenic acid induces synergistic loss of rat hippocampal neurons. Neuroscience 84:479–487
Nehlig A (2013) The neuroprotective effects of cocoa flavanol and its influence on cognitive performance. Br J Clin Pharmacol 75:716–727
Pan S, Liu L, Pan H, Ma Y, Wang D, Kang K, Wang J, Sun B, Sun X, Jiang H (2013) Protective effects of hydroxytyrosol on liver ischemia/reperfusion injury in mice. Mol Nutr Food Res 57:1218–1227
Paxinos G, Franklin KBJ (2001) The Mouse Brain in Stereotaxic Coordinates, 2nd edn. Elsevier, New York
Praticò D (2013) Alzheimer’s disease and the quest for its biological measures. J Alzheimers Dis 33(Suppl 1):S237–S241
Ristagno G, Fumagalli F, Porretta-Serapiglia C, Orrù A, Cassina C, Pesaresi M, Masson S, Villanova L, Merendino A, Villanova A, Cervo L, Lauria G, Latini R, Bianchi R (2012) Hydroxytyrosol attenuates peripheral neuropathy in streptozotocin-induced diabetes in rats. J Agric Food Chem 60:5859–5865
Rouissi K, Hamrita B, Kouidi S, Messai Y, Jaouadi B, Hamden K, Medimegh I, Ouerhani S, Cherif M, Elgaaied AB (2011) In vivo prevention of bladder urotoxicity: purified hydroxytyrosol ameliorates urotoxic effects of cyclophosphamide and buthionine sulfoximine in mice. Int J Toxicol 30:419–427
Sáez ET, Pehar M, Vargas MR, Barbeito L, Maccioni RB (2006) Production of nerve growth factor by beta-amyloid-stimulated astrocytes induces p75NTR-dependent tau hyperphosphorylation in cultured hippocampal neurons. J Neurosci Res 84:1098–1106
Satoh Y, Endo S, Ikeda T, Yamada K, Ito M, Kuroki M, Hiramoto T, Imamura O, Kobayashi Y, Watanabe Y, Itohara S, Takishima K (2007) Extracellular signal-regulated kinase 2 (ERK2) knockdown mice show deficits in long-term memory; ERK2 has a specific function in learning and memory. J Neurosci 27:10765–10776
Schaffer S, Podstawa M, Visioli F, Bogani P, Müller WE, Eckert GP (2007) Hydroxytyrosol-rich olive mill wastewater extract protects brain cells in vitro and ex vivo. J Agric Food Chem 55:5043–5049
Schmitt WB, Deacon RM, Seeburg PH, Rawlins JN, Bannerman DM (2003) A within-subjects, within-task demonstration of intact spatial reference memory and impaired spatial working memory in glutamate receptor-A-deficient mice. J Neurosci 23:3953–3959
Sclip A, Antoniou X, Colombo A, Camici GG, Pozzi L, Cardinetti D, Feligioni M, Veglianese P, Bahlmann FH, Cervo L, Balducci C, Costa C, Tozzi A, Calabresi P, Forloni G, Borsello T (2011) c-Jun N-terminal kinase regulates soluble Aβ oligomers and cognitive impairment in AD mouse model. J Biol Chem 286:43871–43880
Signorile A, Micelli L, De Rasmo D, Santeramo A, Papa F, Ficarella R, Gattoni G, Scacco S, Papa S (2014) Regulation of the biogenesis of OXPHOS complexes in cell transition from replicating to quiescent state: involvement of PKA and effect of hydroxytyrosol. Biochim Biophys Acta 1843:675–684
St-Laurent-Thibault C, Arseneault M, Longpré F, Ramassamy C (2011) Tyrosol and hydroxytyrosol, two main components of olive oil, protect N2a cells against amyloid-β-induced toxicity. Involvement of the NF-κB signaling. Curr Alzheimer Res 8:543–551
Tan YW, Zhang SJ, Hoffmann T, Bading H (2012) Increasing levels of wild-type CREB up-regulates several activity-regulated inhibitor of death (AID) genes and promotes neuronal survival. BMC Neurosci 13:48
Wang Y, Tang XC, Zhang HY (2012) Huperzine A alleviates synaptic deficits and modulates amyloidogenic and nonamyloidogenic pathways in APPswe/PS1dE9 transgenic mice. J Neurosci Res 90:508–517
Watson K, Fan GH (2005) Macrophage inflammatory protein 2 inhibits beta-amyloid peptide (1–42)-mediated hippocampal neuronal apoptosis through activation of mitogen-activated protein kinase and phosphatidylinositol 3-kinase signaling pathways. Mol Pharmacol 67:757–765
Yu X, Wang LN, Ma L, You R, Cui R, Ji D, Wu Y, Zhang CF, Yang ZL, Ji H (2012) Akebia saponin D attenuates ibotenic acid-induced cognitive deficits and pro-apoptotic response in rats: involvement of MAPK signal pathway. Pharmacol Biochem Behav 101:479–486
Yue XH, Liu XJ, Wu MN, Chen JY, Qi JS (2014) Amyloid β protein suppresses hippocampal theta rhythm and induces behavioral disinhibition and spatial memory deficit in rats. Sheng Li Xue Bao 66:97–106
Zhang LL, Sui HJ, Liang B, Wang HM, Qu WH, Yu SX, Jin Y (2014) Atorvastatin prevents amyloid-β peptide oligomer-induced synaptotoxicity and memory dysfunction in rats through a p38 MAPK-dependent pathway. Acta Pharmacol Sin. doi:10.1038/aps.2013.203
Zhao B, Ma Y, Xu Z, Wang J, Wang F, Wang D, Pan S, Wu Y, Pan H, Xu D, Liu L, Jiang H (2014) Hydroxytyrosol, a natural molecule from olive oil, suppresses the growth of human hepatocellular carcinoma cells via inactivating AKT and nuclear factor-kappa B pathways. Cancer Lett 347:79–87
Zhu L, Liu Z, Feng Z, Hao J, Shen W, Li X, Sun L, Sharman E, Wang Y, Wertz K, Weber P, Shi X, Liu J (2010) Hydroxytyrosol protects against oxidative damage by simultaneous activation of mitochondrial biogenesis and phase II detoxifying enzyme systems in retinal pigment epithelial cells. J Nutr Biochem 21:1089–1098
Conflict of interest
The authors declare no potential conflict of interest.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Arunsundar, M., Shanmugarajan, T.S. & Ravichandran, V. 3,4-Dihydroxyphenylethanol Attenuates Spatio-Cognitive Deficits in an Alzheimer’s Disease Mouse Model: Modulation of the Molecular Signals in Neuronal Survival-Apoptotic Programs. Neurotox Res 27, 143–155 (2015). https://doi.org/10.1007/s12640-014-9492-x
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12640-014-9492-x