Molecular Neurobiology

, Volume 54, Issue 3, pp 1967–1977 | Cite as

Curcumin Ameliorates Memory Decline via Inhibiting BACE1 Expression and β-Amyloid Pathology in 5×FAD Transgenic Mice

  • Kunmu Zheng
  • Xiaoman Dai
  • Nai’an Xiao
  • Xilin Wu
  • Zhen Wei
  • Wenting Fang
  • Yuangui Zhu
  • Jing ZhangEmail author
  • Xiaochun ChenEmail author


Alzheimer’s disease (AD) is the most common dementia and the trigger of its pathological cascade is widely believed to be the overproduction and accumulation of β-amyloid protein (Aβ) in the affected brain. However, effective AD remedies are still anxiously awaited. Recent evidence suggests that curcumin may be a potential agent for AD treatment. In this study, we used 5×FAD transgenic mice as an AD model to investigate the effects of curcumin on AD. Our results showed that curcumin administration (150 or 300 mg/kg/day, intragastrically, for 60 days) dramatically reduced Aβ production by downregulating BACE1 expression, preventing synaptic degradation, and improving spatial learning and memory impairment of 5×FAD mice. These findings suggest that curcumin is a potential candidate for AD treatment.


Alzheimer’s disease (AD) β-Site amyloid precursor protein cleavage enzyme 1 (BACE1) Curcumin β-Amyloid protein (Aβ) 



We thank Prof. Mary Jo LaDu (Department of Anatomy and Cell Biology, University of Illinois at Chicago, USA) for kindly providing the 5×FAD mice. These studies were funded by the National Natural Science Foundation of China to Prof. Xiao-chun Chen (No. 91232709, 811171216, 81110555) and Prof. Jing Zhang (No. 81401149) and the National and Fujian Province’s Key Clinical Specialty Discipline Construction Programs.

Compliance with Ethical Standards

Conflict of Interest

The authors have no conflict of interests to declare.


  1. 1.
    Thies W, Bleiler L, Alzheimer’s A (2013) 2013 Alzheimer’s disease facts and figures. Alzheimers Dement J Alzheimers Assoc 9 (2):208–245. doi:10.1016/j.jalz.2013.02.003Google Scholar
  2. 2.
    Selkoe DJ (2001) Alzheimer’s disease: genes, proteins, and therapy. Physiol Rev 81(2):741–766PubMedGoogle Scholar
  3. 3.
    Small DH, Mok SS, Bornstein JC (2001) Alzheimer’s disease and Abeta toxicity: from top to bottom. Nat Rev Neurosci 2(8):595–598. doi: 10.1038/35086072 CrossRefPubMedGoogle Scholar
  4. 4.
    Zhang YW, Thompson R, Zhang H, Xu H (2011) APP processing in Alzheimer’s disease. Molecular Brain 4:3. doi: 10.1186/1756-6606-4-3 CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Bulloj A, Leal MC, Xu H, Castano EM, Morelli L (2010) Insulin-degrading enzyme sorting in exosomes: a secretory pathway for a key brain amyloid-beta degrading protease. J Alzheimers Dis JAD 19(1):79–95. doi: 10.3233/JAD-2010-1206 CrossRefPubMedGoogle Scholar
  6. 6.
    Hersh LB, Rodgers DW (2008) Neprilysin and amyloid beta peptide degradation. Curr Alzheimer Res 5(2):225–231CrossRefPubMedGoogle Scholar
  7. 7.
    Liang K, Yang L, Yin C, Xiao Z, Zhang J, Liu Y, Huang J (2010) Estrogen stimulates degradation of beta-amyloid peptide by up-regulating neprilysin. J Biol Chem 285(2):935–942. doi: 10.1074/jbc.M109.051664 CrossRefPubMedGoogle Scholar
  8. 8.
    Wang YJ, Pan MH, Cheng AL, Lin LI, Ho YS, Hsieh CY, Lin JK (1997) Stability of curcumin in buffer solutions and characterization of its degradation products. J Pharm Biomed Anal 15(12):1867–1876CrossRefPubMedGoogle Scholar
  9. 9.
    Strimpakos AS, Sharma RA (2008) Curcumin: preventive and therapeutic properties in laboratory studies and clinical trials. Antioxid Redox Signal 10(3):511–545. doi: 10.1089/ars.2007.1769 CrossRefPubMedGoogle Scholar
  10. 10.
    Ramsewak RS, DeWitt DL, Nair MG (2000) Cytotoxicity, antioxidant and anti-inflammatory activities of curcumins I-III from Curcuma longa. Phytomedicine 7(4):303–308. doi: 10.1016/S0944-7113(00)80048-3 CrossRefPubMedGoogle Scholar
  11. 11.
    Ammon HP, Wahl MA (1991) Pharmacology of Curcuma longa. Planta Med 57(1):1–7. doi: 10.1055/s-2006-960004 CrossRefPubMedGoogle Scholar
  12. 12.
    Chandra V, Pandav R, Dodge HH, Johnston JM, Belle SH, DeKosky ST, Ganguli M (2001) Incidence of Alzheimer’s disease in a rural community in India: the Indo-US study. Neurology 57(6):985–989CrossRefPubMedGoogle Scholar
  13. 13.
    Neves G, Cooke SF, Bliss TV (2008) Synaptic plasticity, memory and the hippocampus: a neural network approach to causality. Nat Rev Neurosci 9(1):65–75. doi: 10.1038/nrn2303 CrossRefPubMedGoogle Scholar
  14. 14.
    Kennedy MB (2016) Synaptic signaling in learning and memory. Cold Spring Harbor Perspect Biol 8 (2). doi:10.1101/cshperspect.a016824Google Scholar
  15. 15.
    Scheff SW, Price DA (2003) Synaptic pathology in Alzheimer’s disease: a review of ultrastructural studies. Neurobiol Aging 24(8):1029–1046CrossRefPubMedGoogle Scholar
  16. 16.
    Scheff SW, Price DA (2001) Alzheimer’s disease-related synapse loss in the cingulate cortex. J Alzheimers Dis JAD 3(5):495–505CrossRefPubMedGoogle Scholar
  17. 17.
    Kwon SE, Chapman ER (2011) Synaptophysin regulates the kinetics of synaptic vesicle endocytosis in central neurons. Neuron 70(5):847–854. doi: 10.1016/j.neuron.2011.04.001 CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Gordon SL, Leube RE, Cousin MA (2011) Synaptophysin is required for synaptobrevin retrieval during synaptic vesicle endocytosis. J Neurosci 31(39):14032–14036. doi: 10.1523/JNEUROSCI.3162-11.2011 CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Lacor PN, Buniel MC, Furlow PW, Clemente AS, Velasco PT, Wood M, Viola KL, Klein WL (2007) Abeta oligomer-induced aberrations in synapse composition, shape, and density provide a molecular basis for loss of connectivity in Alzheimer’s disease. J Neurosci 27(4):796–807. doi: 10.1523/JNEUROSCI.3501-06.2007 CrossRefPubMedGoogle Scholar
  20. 20.
    Evans NA, Facci L, Owen DE, Soden PE, Burbidge SA, Prinjha RK, Richardson JC, Skaper SD (2008) Abeta(1-42) reduces synapse number and inhibits neurite outgrowth in primary cortical and hippocampal neurons: a quantitative analysis. J Neurosci Methods 175(1):96–103. doi: 10.1016/j.jneumeth.2008.08.001 CrossRefPubMedGoogle Scholar
  21. 21.
    Freir DB, Fedriani R, Scully D, Smith IM, Selkoe DJ, Walsh DM, Regan CM (2011) Abeta oligomers inhibit synapse remodelling necessary for memory consolidation. Neurobiol Aging 32(12):2211–2218. doi: 10.1016/j.neurobiolaging.2010.01.001 CrossRefPubMedGoogle Scholar
  22. 22.
    Wilcox KC, Lacor PN, Pitt J, Klein WL (2011) Abeta oligomer-induced synapse degeneration in Alzheimer’s disease. Cell Mol Neurobiol 31(6):939–948. doi: 10.1007/s10571-011-9691-4 CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Ono K, Yoshiike Y, Takashima A, Hasegawa K, Naiki H, Yamada M (2003) Potent anti-amyloidogenic and fibril-destabilizing effects of polyphenols in vitro: implications for the prevention and therapeutics of Alzheimer’s disease. J Neurochem 87(1):172–181CrossRefPubMedGoogle Scholar
  24. 24.
    Ling Y, Morgan K, Kalsheker N (2003) Amyloid precursor protein (APP) and the biology of proteolytic processing: relevance to Alzheimer’s disease. Int J Biochem Cell Biol 35(11):1505–1535CrossRefPubMedGoogle Scholar
  25. 25.
    Gandy S, Caporaso G, Buxbaum J, Frangione B, Greengard P (1994) APP processing, A beta-amyloidogenesis, and the pathogenesis of Alzheimer’s disease. Neurobiol Aging 15(2):253–256CrossRefPubMedGoogle Scholar
  26. 26.
    Menendez-Gonzalez M, Perez-Pinera P, Martinez-Rivera M, Calatayud MT, Blazquez Menes B (2005) APP processing and the APP-KPI domain involvement in the amyloid cascade. Neurodegener Dis 2(6):277–283. doi: 10.1159/000092315 CrossRefPubMedGoogle Scholar
  27. 27.
    Cai H, Wang Y, McCarthy D, Wen H, Borchelt DR, Price DL, Wong PC (2001) BACE1 is the major beta-secretase for generation of Abeta peptides by neurons. Nat Neurosci 4(3):233–234. doi: 10.1038/85064 CrossRefPubMedGoogle Scholar
  28. 28.
    Hitt B, Riordan SM, Kukreja L, Eimer WA, Rajapaksha TW, Vassar R (2012) Beta-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1)-deficient mice exhibit a close homolog of L1 (CHL1) loss-of-function phenotype involving axon guidance defects. J Biol Chem 287(46):38408–38425. doi: 10.1074/jbc.M112.415505 CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Luo Y, Bolon B, Kahn S et al (2001) Mice deficient in BACE1, the Alzheimer’s beta-secretase, have normal phenotype and abolished beta-amyloid generation. Nat Neurosci 4(3):231–232. doi: 10.1038/85059 CrossRefPubMedGoogle Scholar
  30. 30.
    Fukumoto H, Cheung BS, Hyman BT, Irizarry MC (2002) Beta-secretase protein and activity are increased in the neocortex in Alzheimer disease. Arch Neurol 59(9):1381–1389CrossRefPubMedGoogle Scholar
  31. 31.
    Holsinger RM, McLean CA, Beyreuther K, Masters CL, Evin G (2002) Increased expression of the amyloid precursor beta-secretase in Alzheimer’s disease. Ann Neurol 51(6):783–786. doi: 10.1002/ana.10208 CrossRefPubMedGoogle Scholar
  32. 32.
    Yang LB, Lindholm K, Yan R et al (2003) Elevated beta-secretase expression and enzymatic activity detected in sporadic Alzheimer disease. Nat Med 9(1):3–4. doi: 10.1038/nm0103-3 CrossRefPubMedGoogle Scholar
  33. 33.
    Chen CH, Zhou W, Liu S et al (2012) Increased NF-kappaB signalling up-regulates BACE1 expression and its therapeutic potential in Alzheimer’s disease. Int J Neuropsychopharmacol 15(1):77–90. doi: 10.1017/S1461145711000149 CrossRefPubMedGoogle Scholar
  34. 34.
    Mei Z, Yan P, Tan X, Zheng S, Situ B (2015) Transcriptional regulation of BACE1 by NFAT3 leads to enhanced amyloidogenic processing. Neurochem Res 40(4):829–836. doi: 10.1007/s11064-015-1533-1 CrossRefPubMedGoogle Scholar
  35. 35.
    Cho HJ, Jin SM, Youn HD, Huh K, Mook-Jung I (2008) Disrupted intracellular calcium regulates BACE1 gene expression via nuclear factor of activated T cells 1 (NFAT 1) signaling. Aging cell 7(2):137–147. doi: 10.1111/j.1474-9726.2007.00360.x CrossRefPubMedGoogle Scholar
  36. 36.
    Cho HJ, Kim SK, Jin SM, Hwang EM, Kim YS, Huh K, Mook-Jung I (2007) IFN-gamma-induced BACE1 expression is mediated by activation of JAK2 and ERK1/2 signaling pathways and direct binding of STAT1 to BACE1 promoter in astrocytes. Glia 55(3):253–262. doi: 10.1002/glia.20451 CrossRefPubMedGoogle Scholar
  37. 37.
    Wen Y, Yu WH, Maloney B et al (2008) Transcriptional regulation of beta-secretase by p25/cdk5 leads to enhanced amyloidogenic processing. Neuron 57(5):680–690. doi: 10.1016/j.neuron.2008.02.024 CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Wang R, Li JJ, Diao S et al (2013) Metabolic stress modulates Alzheimer’s beta-secretase gene transcription via SIRT1-PPARgamma-PGC-1 in neurons. Cell Metab 17(5):685–694. doi: 10.1016/j.cmet.2013.03.016 CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Tu XK, Yang WZ, Chen JP, Chen Y, Ouyang LQ, Xu YC, Shi SS (2014) Curcumin inhibits TLR2/4-NF-kappaB signaling pathway and attenuates brain damage in permanent focal cerebral ischemia in rats. Inflammation 37(5):1544–1551. doi: 10.1007/s10753-014-9881-6 CrossRefPubMedGoogle Scholar
  40. 40.
    Deng Y, Lu X, Wang L et al (2014) Curcumin inhibits the AKT/NF-kappaB signaling via CpG demethylation of the promoter and restoration of NEP in the N2a cell line. AAPS J 16(4):649–657. doi: 10.1208/s12248-014-9605-8 CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Kliem C, Merling A, Giaisi M, Kohler R, Krammer PH, Li-Weber M (2012) Curcumin suppresses T cell activation by blocking Ca2+ mobilization and nuclear factor of activated T cells (NFAT) activation. J Biol Chem 287(13):10200–10209. doi: 10.1074/jbc.M111.318733 CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Rajasingh J, Raikwar HP, Muthian G, Johnson C, Bright JJ (2006) Curcumin induces growth-arrest and apoptosis in association with the inhibition of constitutively active JAK-STAT pathway in T cell leukemia. Biochem Biophys Res Commun 340(2):359–368. doi: 10.1016/j.bbrc.2005.12.014 CrossRefPubMedGoogle Scholar
  43. 43.
    Bharti AC, Donato N, Aggarwal BB (2003) Curcumin (diferuloylmethane) inhibits constitutive and IL-6-inducible STAT3 phosphorylation in human multiple myeloma cells. J Immunol 171(7):3863–3871CrossRefPubMedGoogle Scholar
  44. 44.
    Liu ZJ, Liu HQ, Xiao C, Fan HZ, Huang Q, Liu YH, Wang Y (2014) Curcumin protects neurons against oxygen-glucose deprivation/reoxygenation-induced injury through activation of peroxisome proliferator-activated receptor-gamma function. J Neurosci Res 92(11):1549–1559. doi: 10.1002/jnr.23438 CrossRefPubMedGoogle Scholar
  45. 45.
    Kojro E, Gimpl G, Lammich S, Marz W, Fahrenholz F (2001) Low cholesterol stimulates the nonamyloidogenic pathway by its effect on the alpha-secretase ADAM 10. Proc Natl Acad Sci U S A 98(10):5815–5820. doi: 10.1073/pnas.081612998 CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Buxbaum JD, Koo EH, Greengard P (1993) Protein phosphorylation inhibits production of Alzheimer amyloid beta/A4 peptide. Proc Natl Acad Sci U S A 90(19):9195–9198CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Blobel CP (1997) Metalloprotease-disintegrins: links to cell adhesion and cleavage of TNF alpha and Notch. Cell 90(4):589–592CrossRefPubMedGoogle Scholar
  48. 48.
    Hooper NM, Turner AJ (2002) The search for alpha-secretase and its potential as a therapeutic approach to Alzheimer’s disease. Curr Med Chem 9(11):1107–1119CrossRefPubMedGoogle Scholar
  49. 49.
    Buxbaum JD, Liu KN, Luo Y et al (1998) Evidence that tumor necrosis factor alpha converting enzyme is involved in regulated alpha-secretase cleavage of the Alzheimer amyloid protein precursor. The Journal of biological chemistry 273(43):27765–27767CrossRefPubMedGoogle Scholar
  50. 50.
    Lammich S, Kojro E, Postina R, Gilbert S, Pfeiffer R, Jasionowski M, Haass C, Fahrenholz F (1999) Constitutive and regulated alpha-secretase cleavage of Alzheimer’s amyloid precursor protein by a disintegrin metalloprotease. Proc Natl Acad Sci U S A 96(7):3922–3927CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Marcinkiewicz M, Seidah NG (2000) Coordinated expression of beta-amyloid precursor protein and the putative beta-secretase BACE and alpha-secretase ADAM10 in mouse and human brain. J Neurochem 75(5):2133–2143CrossRefPubMedGoogle Scholar
  52. 52.
    Carpentier M, Robitaille Y, DesGroseillers L, Boileau G, Marcinkiewicz M (2002) Declining expression of neprilysin in Alzheimer disease vasculature: possible involvement in cerebral amyloid angiopathy. J Neuropathol Exp Neurol 61(10):849–856CrossRefPubMedGoogle Scholar
  53. 53.
    Miners JS, Baig S, Tayler H, Kehoe PG, Love S (2009) Neprilysin and insulin-degrading enzyme levels are increased in Alzheimer disease in relation to disease severity. J Neuropathol Exp Neurol 68(8):902–914. doi: 10.1097/NEN.0b013e3181afe475 CrossRefPubMedGoogle Scholar
  54. 54.
    Caccamo A, Oddo S, Sugarman MC, Akbari Y, LaFerla FM (2005) Age- and region-dependent alterations in Abeta-degrading enzymes: implications for Abeta-induced disorders. Neurobiol Aging 26(5):645–654. doi: 10.1016/j.neurobiolaging.2004.06.013 CrossRefPubMedGoogle Scholar
  55. 55.
    Hellstrom-Lindahl E, Ravid R, Nordberg A (2008) Age-dependent decline of neprilysin in Alzheimer’s disease and normal brain: inverse correlation with A beta levels. Neurobiol Aging 29(2):210–221. doi: 10.1016/j.neurobiolaging.2006.10.010 CrossRefPubMedGoogle Scholar
  56. 56.
    Wang P, Wang H, Li R, Li Y, Ren Y, Zhu Z, Sun H, Yang J, Sun J (2011) Effect of curcumin on expression of Abeta42 and Abeta-degrading enzyme NEP in APPswe/PS1dE9 double transgenic mice. Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China J Chinese Mater Med 36 (8):1079–1082Google Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Kunmu Zheng
    • 1
    • 2
    • 3
  • Xiaoman Dai
    • 1
    • 2
  • Nai’an Xiao
    • 2
    • 3
  • Xilin Wu
    • 2
  • Zhen Wei
    • 2
  • Wenting Fang
    • 2
  • Yuangui Zhu
    • 1
    • 2
  • Jing Zhang
    • 1
    • 2
    Email author
  • Xiaochun Chen
    • 1
    • 2
    Email author
  1. 1.Department of Neurology and Geriatrics, Fujian Institute of GeriatricsAffiliated Union Hospital of Fujian Medical UniversityFuzhouPeople’s Republic of China
  2. 2.Key Laboratory of Brain Aging and Neurodegenerative Diseases, Fujian Key Laboratory of Molecular NeurologyFujian Medical UniversityFuzhouChina
  3. 3.Department of NeurologyThe First Affiliated Hospital of Xiamen UniversityXiamenChina

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