Advertisement

Hesperetin Confers Neuroprotection by Regulating Nrf2/TLR4/NF-κB Signaling in an Aβ Mouse Model

  • Muhammad Ikram
  • Tahir Muhammad
  • Shafiq Ur Rehman
  • Amjad Khan
  • Min Gi Jo
  • Tahir Ali
  • Myeong Ok KimEmail author
Article
  • 180 Downloads

Abstract

Hesperetin is a bioactive flavonoid in the body, produced from hesperidin. No comprehensive studies have shown its protective effects in neurodegenerative disorders. Here, we hypothesized that hesperetin may protect the mice brain against Aβ-induced neurodegeneration. Twenty-four hours after intracerebroventricular injection of Aβ1-42, the treated group was injected hesperetin. For in vitro experiments, HT22 and BV-2 cells were used. Immunoblot, immunofluorescence, and behavioral analyses were used to evaluate the different parameters. Our results indicated that hesperetin significantly attenuated oxidative stress, as assessed by the expression of Nrf2/HO-1 and LPO and ROS assays, in the hippocampus, cortex, and in vitro HT22 cells. Similarly, activated glial cells were regulated by hesperetin, as assessed by the expression of GFAP and Iba-1. Moreover, the expression of TLR4, p-NF-κB, and downstream targets was analyzed; the results showed that hesperetin reinstated the expression of these markers. The effects of hesperetin were further confirmed by using specific TLR4 and p-NF-κB inhibitors in BV-2 cells. Next, we evaluated Aβ pathology in the cortex, hippocampus, and HT22 cells, showing that hesperetin significantly reduced the Aβ pathology. Furthermore, the antiapoptotic effects of hesperetin were assessed, which showed strong antiapoptotic effects. Overall, the neuroprotective effect of hesperetin was found to be a multipotent effect, involving the inhibition of oxidative stress, neuroinflammation, apoptotic cell death, and cognitive consolidation. Given antioxidant, anti-inflammatory, and antiapoptotic potentials against Aβ-induced neurodegeneration and memory impairment, hesperetin may be a promising therapeutic agent for Alzheimer’s disease–like neurological disorders.

Keywords

Amyloid beta Neuroinflammation Neurodegeneration Hesperetin Neuroprotection 

Abbreviations

Nrf2

nuclear factor erythroid 2-related factor 2

HO-1

heme oxygenase 1

TLR4

Toll-like receptor 4

TNF-α

tissue necrosis factor-α

AD

Alzheimer’s disease

CNS

central nervous system

amyloid beta

PBS

phosphate buffer saline

SDS-PAGE

sodium dodecyl sulfate-polyacrylamide gel electrophoresis

FITC

fluorescein isothiocyanate

TRITC

tetramethylrhodamine isothiocyanate

DAPI

4′,6-diamidino-2-phenylindole

Notes

Author Contributions

MI: Concept, design, data collection, analysis, interpretation, and manuscript writing.

TM: Mice grouping, treatment, and performed in vitro experiments.

SUR: Mice grouping, manuscript evaluation, and interpretation.

AK: Mice treatment and behavioral studies.

TA: Data collection and analysis.

MGJ: Behavioral studies, animal handling, and treatment.

MOK: The corresponding author, reviewed and approved the manuscript, and holds all the responsibilities related to this manuscript. All the authors reviewed the revised manuscript.

Funding Information

This research work was supported by the Brain Research Program through the National Research Foundation of Korea funded by the Ministry of Science, ICT & Future Planning (2016M3C7A1904391).

Compliance with Ethical Standards

The animal maintenance, treatments, behavioral studies, and surgical procedures were carried out in accordance with the animal ethics committee (IACUC) guidelines issued by the Division of Applied Life Sciences, Department of Biology at Gyeongsang National University, South Korea. The experimental methods were carried out in accordance with the approved 22 guidelines (Approval ID: 125) and all experimental protocols were approved by the animal ethics committee (IACUC) of the Division of Applied Life Sciences, Department of Biology at Gyeongsang National University, South Korea.

Conflict of Interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Nistico R, Pignatelli M, Piccinin S, Mercuri NB, Collingridge G (2012) Targeting synaptic dysfunction in Alzheimer’s disease therapy. Mol Neurobiol 46(3):572–587.  https://doi.org/10.1007/s12035-012-8324-3 CrossRefPubMedGoogle Scholar
  2. 2.
    Dheer Y, Chitranshi N, Gupta V, Abbasi M, Mirzaei M, You Y, Chung R, Graham SL et al (2018) Bexarotene modulates retinoid-X-receptor expression and is protective against neurotoxic endoplasmic reticulum stress response and apoptotic pathway activation. Mol Neurobiol 55(12):9043–9056.  https://doi.org/10.1007/s12035-018-1041-9 CrossRefPubMedGoogle Scholar
  3. 3.
    Tamano H, Suzuki H, Murakami T, Fujii H, Adlard PA, Bush AI, Takeda A (2018) Amyloid beta1-42-induced rapid Zn(2+) influx into dentate granule cells attenuates maintained LTP followed by retrograde amnesia. Mol Neurobiol.  https://doi.org/10.1007/s12035-018-1429-6
  4. 4.
    Dong S, Huang X, Zhen J, Van Halm-Lutterodt N, Wang J, Zhou C, Yuan L (2018) Dietary vitamin E status dictates oxidative stress outcomes by modulating effects of fish oil supplementation in Alzheimer disease model APPswe/PS1dE9 mice. Mol Neurobiol 55(12):9204–9219.  https://doi.org/10.1007/s12035-018-1060-6 CrossRefPubMedGoogle Scholar
  5. 5.
    Ayaz M, Junaid M, Ullah F, Subhan F, Sadiq A, Ali G, Ovais M, Shahid M et al (2017) Anti-Alzheimer’s studies on beta-sitosterol isolated from Polygonum hydropiper L. Front Pharmacol 8:697.  https://doi.org/10.3389/fphar.2017.00697 CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Uddin MS, Al Mamun A, Kabir MT, Jakaria M, Mathew B, Barreto GE, Ashraf GM (2018) Nootropic and anti-Alzheimer’s actions of medicinal plants: molecular insight into therapeutic potential to alleviate Alzheimer’s neuropathology. Mol Neurobiol.  https://doi.org/10.1007/s12035-018-1420-2
  7. 7.
    Ali T, Yoon GH, Shah SA, Lee HY, Kim MO (2015) Osmotin attenuates amyloid beta-induced memory impairment, tau phosphorylation and neurodegeneration in the mouse hippocampus. Sci Rep 5:11708.  https://doi.org/10.1038/srep11708 CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Kumar A, Singh A, Ekavali (2015) A review on Alzheimer’s disease pathophysiology and its management: an update. Pharmacol Rep 67(2):195–203.  https://doi.org/10.1016/j.pharep.2014.09.004 CrossRefGoogle Scholar
  9. 9.
    Godoy JA, Lindsay CB, Quintanilla RA, Carvajal FJ, Cerpa W, Inestrosa NC (2017) Quercetin exerts differential neuroprotective effects against H2O2 and Abeta aggregates in hippocampal neurons: the role of mitochondria. Mol Neurobiol 54(9):7116–7128.  https://doi.org/10.1007/s12035-016-0203-x CrossRefPubMedGoogle Scholar
  10. 10.
    Barage SH, Sonawane KD (2015) Amyloid cascade hypothesis: Pathogenesis and therapeutic strategies in Alzheimer’s disease. Neuropeptides 52:1–18.  https://doi.org/10.1016/j.npep.2015.06.008 CrossRefGoogle Scholar
  11. 11.
    Alkadhi KA, Dao AT (2018) Effect of exercise and Abeta protein infusion on long-term memory-related signaling molecules in hippocampal areas. Mol Neurobiol.  https://doi.org/10.1007/s12035-018-1425-x
  12. 12.
    Cheignon C, Tomas M, Bonnefont-Rousselot D, Faller P, Hureau C, Collin F (2018) Oxidative stress and the amyloid beta peptide in Alzheimer’s disease. Redox Biol 14:450–464.  https://doi.org/10.1016/j.redox.2017.10.014 CrossRefPubMedGoogle Scholar
  13. 13.
    Frost GR, Li YM (2017) The role of astrocytes in amyloid production and Alzheimer’s disease. Open Biol 7(12).  https://doi.org/10.1098/rsob.170228
  14. 14.
    Dwivedi S, Rajasekar N, Hanif K, Nath C, Shukla R (2016) Sulforaphane ameliorates okadaic acid-induced memory impairment in rats by activating the Nrf2/HO-1 antioxidant pathway. Mol Neurobiol 53(8):5310–5323.  https://doi.org/10.1007/s12035-015-9451-4 CrossRefPubMedGoogle Scholar
  15. 15.
    Dinkova-Kostova AT, Abramov AY (2015) The emerging role of Nrf2 in mitochondrial function. Free Radic Biol Med 88(Pt B):179–188.  https://doi.org/10.1016/j.freeradbiomed.2015.04.036 CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Ding Y, Chen M, Wang M, Li Y, Wen A (2015) Posttreatment with 11-keto-beta-boswellic acid ameliorates cerebral ischemia-reperfusion injury: Nrf2/HO-1 pathway as a potential mechanism. Mol Neurobiol 52(3):1430–1439.  https://doi.org/10.1007/s12035-014-8929-9 CrossRefPubMedGoogle Scholar
  17. 17.
    Walker DG, Link J, Lue LF, Dalsing-Hernandez JE, Boyes BE (2006) Gene expression changes by amyloid beta peptide-stimulated human postmortem brain microglia identify activation of multiple inflammatory processes. J Leukoc Biol 79(3):596–610.  https://doi.org/10.1189/jlb.0705377 CrossRefPubMedGoogle Scholar
  18. 18.
    Rogers J, Strohmeyer R, Kovelowski CJ, Li R (2002) Microglia and inflammatory mechanisms in the clearance of amyloid beta peptide. Glia 40(2):260–269.  https://doi.org/10.1002/glia.10153 CrossRefPubMedGoogle Scholar
  19. 19.
    Eikelenboom P, Bate C, Van Gool WA, Hoozemans JJ, Rozemuller JM, Veerhuis R, Williams A (2002) Neuroinflammation in Alzheimer’s disease and prion disease. Glia 40(2):232–239.  https://doi.org/10.1002/glia.10146 CrossRefPubMedGoogle Scholar
  20. 20.
    Cameron B, Landreth GE (2010) Inflammation, microglia, and Alzheimer’s disease. Neurobiol Dis 37(3):503–509.  https://doi.org/10.1016/j.nbd.2009.10.006 CrossRefPubMedGoogle Scholar
  21. 21.
    Yamamoto M, Takeda K (2010) Current views of toll-like receptor signaling pathways. Gastroenterol Res Pract 2010:240365.  https://doi.org/10.1155/2010/240365 CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Lehnardt S (2010) Innate immunity and neuroinflammation in the CNS: the role of microglia in Toll-like receptor-mediated neuronal injury. Glia 58(3):253–263.  https://doi.org/10.1002/glia.20928 CrossRefPubMedGoogle Scholar
  23. 23.
    Hanke ML, Kielian T (2011) Toll-like receptors in health and disease in the brain: mechanisms and therapeutic potential. Clin Sci (Lond) 121(9):367–387.  https://doi.org/10.1042/CS20110164 CrossRefGoogle Scholar
  24. 24.
    Frank S, Copanaki E, Burbach GJ, Muller UC, Deller T (2009) Differential regulation of toll-like receptor mRNAs in amyloid plaque-associated brain tissue of aged APP23 transgenic mice. Neurosci Lett 453(1):41–44.  https://doi.org/10.1016/j.neulet.2009.01.075 CrossRefPubMedGoogle Scholar
  25. 25.
    Jin JJ, Kim HD, Maxwell JA, Li L, Fukuchi K (2008) Toll-like receptor 4-dependent upregulation of cytokines in a transgenic mouse model of Alzheimer’s disease. J Neuroinflammation 5:23.  https://doi.org/10.1186/1742-2094-5-23 CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Olson JK, Miller SD (2004) Microglia initiate central nervous system innate and adaptive immune responses through multiple TLRs. J Immunol 173(6):3916–3924.  https://doi.org/10.4049/jimmunol.173.6.3916 CrossRefPubMedGoogle Scholar
  27. 27.
    Michaud JP, Halle M, Lampron A, Theriault P, Prefontaine P, Filali M, Tribout-Jover P, Lanteigne AM et al (2013) Toll-like receptor 4 stimulation with the detoxified ligand monophosphoryl lipid A improves Alzheimer’s disease-related pathology. Proc Natl Acad Sci U S A 110(5):1941–1946.  https://doi.org/10.1073/pnas.1215165110 CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Liu S, Liu Y, Hao W, Wolf L, Kiliaan AJ, Penke B, Rube CE, Walter J et al (2012) TLR2 is a primary receptor for Alzheimer’s amyloid beta peptide to trigger neuroinflammatory activation. J Immunol 188(3):1098–1107.  https://doi.org/10.4049/jimmunol.1101121 CrossRefPubMedGoogle Scholar
  29. 29.
    Zhao B (2005) Natural antioxidants for neurodegenerative diseases. Mol Neurobiol 31(1–3):283–293.  https://doi.org/10.1385/MN:31:1-3:283 CrossRefPubMedGoogle Scholar
  30. 30.
    Lan X, Han X, Li Q, Wang J (2017) Epicatechin, a natural flavonoid compound, protects astrocytes against hemoglobin toxicity via Nrf2 and AP-1 signaling pathways. Mol Neurobiol 54(10):7898–7907.  https://doi.org/10.1007/s12035-016-0271-y CrossRefPubMedGoogle Scholar
  31. 31.
    Jung KY, Park J, Han YS, Lee YH, Shin SY, Lim Y (2017) Synthesis and biological evaluation of hesperetin derivatives as agents inducing apoptosis. Bioorg Med Chem 25(1):397–407.  https://doi.org/10.1016/j.bmc.2016.11.006 CrossRefPubMedGoogle Scholar
  32. 32.
    Garg A, Garg S, Zaneveld LJ, Singla AK (2001) Chemistry and pharmacology of the Citrus bioflavonoid hesperidin. Phytother Res 15(8):655–669CrossRefGoogle Scholar
  33. 33.
    Pollard SE, Whiteman M, Spencer JP (2006) Modulation of peroxynitrite-induced fibroblast injury by hesperetin: a role for intracellular scavenging and modulation of ERK signalling. Biochem Biophys Res Commun 347(4):916–923.  https://doi.org/10.1016/j.bbrc.2006.06.153 CrossRefPubMedGoogle Scholar
  34. 34.
    Rainey-Smith S, Schroetke LW, Bahia P, Fahmi A, Skilton R, Spencer JP, Rice-Evans C, Rattray M et al (2008) Neuroprotective effects of hesperetin in mouse primary neurones are independent of CREB activation. Neurosci Lett 438(1):29–33.  https://doi.org/10.1016/j.neulet.2008.04.056 CrossRefPubMedGoogle Scholar
  35. 35.
    Choi EJ, Ahn WS (2008) Neuroprotective effects of chronic hesperetin administration in mice. Arch Pharm Res 31(11):1457–1462.  https://doi.org/10.1007/s12272-001-2130-1 CrossRefPubMedGoogle Scholar
  36. 36.
    Amin FU, Shah SA, Kim MO (2017) Vanillic acid attenuates Abeta1-42-induced oxidative stress and cognitive impairment in mice. Sci Rep 7:40753.  https://doi.org/10.1038/srep40753 CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Carvalho FB, Gutierres JM, Bueno A, Agostinho P, Zago AM, Vieira J, Fruhauf P, Cechella JL et al (2017) Anthocyanins control neuroinflammation and consequent memory dysfunction in mice exposed to lipopolysaccharide. Mol Neurobiol 54(5):3350–3367.  https://doi.org/10.1007/s12035-016-9900-8 CrossRefPubMedGoogle Scholar
  38. 38.
    Ali T, Kim MJ, Rehman SU, Ahmad A, Kim MO (2017) Anthocyanin-loaded PEG-gold nanoparticles enhanced the neuroprotection of anthocyanins in an Abeta1-42 mouse model of Alzheimer’s disease. Mol Neurobiol 54(8):6490–6506.  https://doi.org/10.1007/s12035-016-0136-4 CrossRefPubMedGoogle Scholar
  39. 39.
    Rehman SU, Shah SA, Ali T, Chung JI, Kim MO (2017) Anthocyanins reversed D-galactose-induced oxidative stress and neuroinflammation mediated cognitive impairment in adult rats. Mol Neurobiol 54(1):255–271.  https://doi.org/10.1007/s12035-015-9604-5 CrossRefPubMedGoogle Scholar
  40. 40.
    Jo MG, Ikram M, Jo MH, Yoo L, Chung KC, Nah SY, Hwang H, Rhim H et al (2018) Gintonin mitigates MPTP-induced loss of nigrostriatal dopaminergic neurons and accumulation of alpha-synuclein via the Nrf2/HO-1 pathway. Mol Neurobiol 56:39–55.  https://doi.org/10.1007/s12035-018-1020-1 CrossRefPubMedGoogle Scholar
  41. 41.
    Liu L, Fujimoto M, Nakano F, Nishikawa H, Okada T, Kawakita F, Imanaka-Yoshida K, Yoshida T et al (2018) Deficiency of tenascin-C alleviates neuronal apoptosis and neuroinflammation after experimental subarachnoid hemorrhage in mice. Mol Neurobiol 55(11):8346–8354.  https://doi.org/10.1007/s12035-018-1006-z CrossRefPubMedGoogle Scholar
  42. 42.
    Abid NB, Yoon G, Kim MO (2017) Molecular cloning and expression of osmotin in a baculovirus-insect system: purified osmotin mitigates amyloid-beta deposition in neuronal cells. Sci Rep 7(1):8147.  https://doi.org/10.1038/s41598-017-08396-x CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Liu Y, Walter S, Stagi M, Cherny D, Letiembre M, Schulz-Schaeffer W, Heine H, Penke B et al (2005) LPS receptor (CD14): a receptor for phagocytosis of Alzheimer’s amyloid peptide. Brain 128(Pt 8):1778–1789.  https://doi.org/10.1093/brain/awh531 CrossRefPubMedGoogle Scholar
  44. 44.
    Ali T, Kim T, Rehman SU, Khan MS, Amin FU, Khan M, Ikram M, Kim MO (2017) Natural dietary supplementation of anthocyanins via PI3K/Akt/Nrf2/HO-1 pathways mitigate oxidative stress, neurodegeneration, and memory impairment in a mouse model of Alzheimer’s disease. Mol Neurobiol 55:6076–6093.  https://doi.org/10.1007/s12035-017-0798-6 CrossRefPubMedGoogle Scholar
  45. 45.
    Muhammad T, Ali T, Ikram M, Khan A, Alam SI, Kim MO (2018) Melatonin rescue oxidative stress-mediated neuroinflammation/ neurodegeneration and memory impairment in scopolamine-induced amnesia mice model. J NeuroImmune Pharmacol.  https://doi.org/10.1007/s11481-018-9824-3
  46. 46.
    Khan MS, Ali T, Kim MW, Jo MH, Chung JI, Kim MO (2018) Anthocyanins improve hippocampus-dependent memory function and prevent neurodegeneration via JNK/Akt/GSK3beta signaling in LPS-treated adult mice. Mol Neurobiol 56:671–687.  https://doi.org/10.1007/s12035-018-1101-1 CrossRefPubMedGoogle Scholar
  47. 47.
    Gao H-M, Liu B, Zhang W, Hong J-S (2003) Novel anti-inflammatory therapy for Parkinson’s disease. Trends Pharmacol Sci 24(8):395–401.  https://doi.org/10.1016/s0165-6147(03)00176-7 CrossRefPubMedGoogle Scholar
  48. 48.
    Tang SC, Lathia JD, Selvaraj PK, Jo DG, Mughal MR, Cheng A, Siler DA, Markesbery WR et al (2008) Toll-like receptor-4 mediates neuronal apoptosis induced by amyloid beta-peptide and the membrane lipid peroxidation product 4-hydroxynonenal. Exp Neurol 213(1):114–121.  https://doi.org/10.1016/j.expneurol.2008.05.014 CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Yu MS, Suen KC, Kwok NS, So KF, Hugon J, Chang RC (2006) Beta-amyloid peptides induces neuronal apoptosis via a mechanism independent of unfolded protein responses. Apoptosis 11(5):687–700.  https://doi.org/10.1007/s10495-006-5540-1 CrossRefPubMedGoogle Scholar
  50. 50.
    Moser VA, Uchoa MF, Pike CJ (2018) TLR4 inhibitor TAK-242 attenuates the adverse neural effects of diet-induced obesity. J Neuroinflammation 15(1):306.  https://doi.org/10.1186/s12974-018-1340-0 CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Rapoport M, Dawson HN, Binder LI, Vitek MP, Ferreira A (2002) Tau is essential to beta -amyloid-induced neurotoxicity. Proc Natl Acad Sci U S A 99(9):6364–6369.  https://doi.org/10.1073/pnas.092136199 CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Gotz J, Gotz NN (2009) Animal models for Alzheimer’s disease and frontotemporal dementia: a perspective. ASN Neuro 1(4):AN20090042.  https://doi.org/10.1042/AN20090042 CrossRefGoogle Scholar
  53. 53.
    Chun YS, Zhang L, Li H, Park Y, Chung S, Yang HO (2018) 7-Deoxy-trans-dihydronarciclasine reduces beta-amyloid and ameliorates memory impairment in a transgenic model of Alzheimer’s disease. Mol Neurobiol 55(12):8953–8964.  https://doi.org/10.1007/s12035-018-1023-y CrossRefPubMedGoogle Scholar
  54. 54.
    Cuadrado-Tejedor M, Garcia-Osta A (2014) Current animal models of Alzheimer’s disease: challenges in translational research. Front Neurol 5:182.  https://doi.org/10.3389/fneur.2014.00182 CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Matsumura A, Emoto MC, Suzuki S, Iwahara N, Hisahara S, Kawamata J, Suzuki H, Yamauchi A et al (2015) Evaluation of oxidative stress in the brain of a transgenic mouse model of Alzheimer disease by in vivo electron paramagnetic resonance imaging. Free Radic Biol Med 85:165–173.  https://doi.org/10.1016/j.freeradbiomed.2015.04.013 CrossRefPubMedGoogle Scholar
  56. 56.
    Barbagallo M, Marotta F, Dominguez LJ (2015) Oxidative stress in patients with Alzheimer’s disease: effect of extracts of fermented papaya powder. Mediat Inflamm 2015:624801.  https://doi.org/10.1155/2015/624801 CrossRefGoogle Scholar
  57. 57.
    Mittal M, Siddiqui MR, Tran K, Reddy SP, Malik AB (2014) Reactive oxygen species in inflammation and tissue injury. Antioxid Redox Signal 20(7):1126–1167.  https://doi.org/10.1089/ars.2012.5149 CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Gonzalez-Reyes RE, Nava-Mesa MO, Vargas-Sanchez K, Ariza-Salamanca D, Mora-Munoz L (2017) Involvement of astrocytes in Alzheimer’s disease from a neuroinflammatory and oxidative stress perspective. Front Mol Neurosci 10:427.  https://doi.org/10.3389/fnmol.2017.00427 CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Bao LH, Zhang YN, Zhang JN, Gu L, Yang HM, Huang YY, Xia N, Zhang H (2018) Urate inhibits microglia activation to protect neurons in an LPS-induced model of Parkinson’s disease. J Neuroinflammation 15(1):131.  https://doi.org/10.1186/s12974-018-1175-8 CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Lee CC, Chang CP, Lin CJ, Lai HL, Kao YH, Cheng SJ, Chen HM, Liao YP et al (2018) Adenosine augmentation evoked by an ENT1 inhibitor improves memory impairment and neuronal plasticity in the APP/PS1 mouse model of Alzheimer’s disease. Mol Neurobiol 55(12):8936–8952.  https://doi.org/10.1007/s12035-018-1030-z CrossRefPubMedGoogle Scholar
  61. 61.
    Garwood CJ, Pooler AM, Atherton J, Hanger DP, Noble W (2011) Astrocytes are important mediators of Abeta-induced neurotoxicity and tau phosphorylation in primary culture. Cell Death Dis 2:e167.  https://doi.org/10.1038/cddis.2011.50 CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Morishima Y, Gotoh Y, Zieg J, Barrett T, Takano H, Flavell R, Davis RJ, Shirasaki Y et al (2001) Beta-amyloid induces neuronal apoptosis via a mechanism that involves the c-Jun N-terminal kinase pathway and the induction of Fas ligand. J Neurosci 21(19):7551–7560CrossRefGoogle Scholar
  63. 63.
    Shankar GM, Walsh DM (2009) Alzheimer’s disease: synaptic dysfunction and Abeta. Mol Neurodegener 4:48.  https://doi.org/10.1186/1750-1326-4-48 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Division of Life Science and Applied Life Science (BK21 plus), College of Natural SciencesGyeongsang National UniversityJinjuRepublic of Korea

Personalised recommendations