Genes & Nutrition

, 9:397

Adenosine triphosphate concentrations are higher in the brain of APOE3- compared to APOE4-targeted replacement mice and can be modulated by curcumin

  • Dawn Chin
  • Stephanie Hagl
  • Annika Hoehn
  • Patricia Huebbe
  • Kathrin Pallauf
  • Tilman Grune
  • Jan Frank
  • Gunter P. Eckert
  • Gerald Rimbach
Research Paper

Abstract

Curcumin from Curcuma longa may exert putative neuroprotective properties in the brain. Impaired mitochondrial function is implicated in Alzheimer’s disease and the presence of the apolipoprotein (APO) E4 genotype, which is a risk factor for late-onset Alzheimer’s disease, may aggravate mitochondrial malfunction. Here, we report that in the brain of 16-month-old APOE4-targeted replacement mice, adenosine triphosphate (ATP) concentrations were significantly lower than in APOE3 mice. A 3-month dietary supplementation of 0.2 % curcumin numerically increased ATP concentrations in APOE3 and significantly in APOE4 mice compared to the respective controls. Curcumin significantly induced the transcription of peroxisome proliferator-activated receptor (PPAR) γ and mitochondrial transcription factor A (TFAM) in APOE3, but not in APOE4 mice. Moreover, PPARγ coactivator (PGC)-1α and guanine–adenine repeat binding protein α (GABPa) mRNA was only increased in APOE3 mice. Consistent with these observations, protein expression of mitochondrial respiratory complexes, especially of complex IV, also appeared to be increased in APOE3 mice. In conclusion, we provide evidence that curcumin affects mitochondrial function and gene and protein expression in the murine brain despite its low bioavailability and carriers of the Alzheimer’s disease-risk genotype APOE4 may be less responsive to dietary curcumin than APOE3 carriers.

Keywords

Curcumin APOE Mitochondrial function ATP synthesis Mice 

References

  1. Anand P, Kunnumakkara AB, Newman RA, Aggarwal BB (2007) Bioavailability of curcumin: problems and promises. Mol Pharm 4(6):807–818. doi:10.1021/mp700113r PubMedCrossRefGoogle Scholar
  2. Baum L, Lam CW, Cheung SK, Kwok T, Lui V, Tsoh J, Lam L, Leung V, Hui E, Ng C, Woo J, Chiu HF, Goggins WB, Zee BC, Cheng KF, Fong CY, Wong A, Mok H, Chow MS, Ho PC, Ip SP, Ho CS, Yu XW, Lai CY, Chan MH, Szeto S, Chan IH, Mok V (2008) Six-month randomized, placebo-controlled, double-blind, pilot clinical trial of curcumin in patients with Alzheimer disease. J Clin Psychopharmacol 28(1):110–113. doi:10.1097/jcp.0b013e318160862c PubMedCrossRefGoogle Scholar
  3. Bhawana Basniwal RK, Buttar HS, Jain VK, Jain N (2011) Curcumin nanoparticles: preparation, characterization, and antimicrobial study. J Agric Food Chem 59(5):2056–2061. doi:10.1021/jf104402t PubMedCrossRefGoogle Scholar
  4. Boesch-Saadatmandi C, Wolffram S, Minihane AM, Rimbach G (2009) Effect of apoE genotype and dietary quercetin on blood lipids and TNF-alpha levels in apoE3 and apoE4 targeted gene replacement mice. Br J Nutr 101(10):1440–1443. doi:10.1017/S0007114508102434 PubMedCrossRefGoogle Scholar
  5. Calabrese V, Cornelius C, Dinkova-Kostova AT, Calabrese EJ, Mattson MP (2010) Cellular stress responses, the hormesis paradigm, and vitagenes: novel targets for therapeutic intervention in neurodegenerative disorders. Antioxid Redox Signal 13(11):1763–1811. doi:10.1089/ars.2009.3074 PubMedCentralPubMedCrossRefGoogle Scholar
  6. Chandra V, Ganguli M, Pandav R, Johnston J, Belle S, DeKosky ST (1998) Prevalence of Alzheimer’s disease and other dementias in rural India: the Indo-US study. Neurology 51(4):1000–1008PubMedCrossRefGoogle Scholar
  7. 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):985–989PubMedCrossRefGoogle Scholar
  8. Chen HK, Ji ZS, Dodson SE, Miranda RD, Rosenblum CI, Reynolds IJ, Freedman SB, Weisgraber KH, Huang Y, Mahley RW (2011) Apolipoprotein E4 domain interaction mediates detrimental effects on mitochondria and is a potential therapeutic target for Alzheimer disease. J Biol Chem 286(7):5215–5221. doi:10.1074/jbc.M110.151084 PubMedCentralPubMedCrossRefGoogle Scholar
  9. Chen HK, Liu Z, Meyer-Franke A, Brodbeck J, Miranda RD, McGuire JG, Pleiss MA, Ji ZS, Balestra ME, Walker DW, Xu Q, Jeong DE, Budamagunta MS, Voss JC, Freedman SB, Weisgraber KH, Huang Y, Mahley RW (2012) Small molecule structure correctors abolish detrimental effects of apolipoprotein E4 in cultured neurons. J Biol Chem 287(8):5253–5266. doi:10.1074/jbc.M111.276162 PubMedCentralPubMedCrossRefGoogle Scholar
  10. Chin D, Huebbe P, Pallauf K, Rimbach G (2013) Neuroprotective properties of curcumin in Alzheimer’s disease–merits and limitations. Curr Med Chem 20(32):3955–3985PubMedCrossRefGoogle Scholar
  11. Chin D, Huebbe P, Frank J, Rimbach G, Pallauf K (2014) Curcumin may impair iron status when fed to mice for six months. Redox Biology. doi:http://dx.doi.org/10.1016/j.redox.2014.01.018
  12. Dikshit P, Goswami A, Mishra A, Chatterjee M, Jana NR (2006) Curcumin induces stress response, neurite outgrowth and prevent NF-kappaB activation by inhibiting the proteasome function. Neurotox Res 9(1):29–37PubMedCrossRefGoogle Scholar
  13. Eckert GP, Renner K, Eckert SH, Eckmann J, Hagl S, Abdel-Kader RM, Kurz C, Leuner K, Muller WE (2012) Mitochondrial dysfunction—a pharmacological target in Alzheimer’s disease. Mol Neurobiol 46(1):136–150. doi:10.1007/s12035-012-8271-z PubMedCrossRefGoogle Scholar
  14. Eckert GP, Schiborr C, Hagl S, Abdel-Kader R, Muller WE, Rimbach G, Frank J (2013) Curcumin prevents mitochondrial dysfunction in the brain of the senescence-accelerated mouse-prone 8. Neurochem Int 62(5):595–602. doi:10.1016/j.neuint.2013.02.014 PubMedCrossRefGoogle Scholar
  15. Esatbeyoglu T, Huebbe P, Ernst IM, Chin D, Wagner AE, Rimbach G (2012) Curcumin—from molecule to biological function. Angew Chem Int Ed Engl 51(22):5308–5332. doi:10.1002/anie.201107724 PubMedCrossRefGoogle Scholar
  16. Hasima N, Aggarwal BB (2013) Targeting proteasomal pathways by dietary curcumin for cancer prevention and treatment. Curr Med Chem. doi:10.2174/09298673113206660135
  17. Hauptmann S, Scherping I, Drose S, Brandt U, Schulz KL, Jendrach M, Leuner K, Eckert A, Muller WE (2009) Mitochondrial dysfunction: an early event in Alzheimer pathology accumulates with age in AD transgenic mice. Neurobiol Aging 30(10):1574–1586. doi:10.1016/j.neurobiolaging.2007.12.005 PubMedCrossRefGoogle Scholar
  18. Hishikawa N, Takahashi Y, Amakusa Y, Tanno Y, Tuji Y, Niwa H, Murakami N, Krishna UK (2012) Effects of turmeric on Alzheimer’s disease with behavioral and psychological symptoms of dementia. Ayu 33(4):499–504. doi:10.4103/0974-8520.110524 PubMedCentralPubMedCrossRefGoogle Scholar
  19. Hondares E, Mora O, Yubero P, Rodriguez de la Concepcion M, Iglesias R, Giralt M, Villarroya F (2006) Thiazolidinediones and rexinoids induce peroxisome proliferator-activated receptor-coactivator (PGC)-1alpha gene transcription: an autoregulatory loop controls PGC-1alpha expression in adipocytes via peroxisome proliferator-activated receptor-gamma coactivation. Endocrinology 147(6):2829–2838. doi:http://www.ncbi.nlm.nih.gov/pubmed/16513826 PubMedCrossRefGoogle Scholar
  20. Huebbe P, Jofre-Monseny L, Boesch-Saadatmandi C, Minihane AM, Rimbach G (2007) Effect of apoE genotype and vitamin E on biomarkers of oxidative stress in cultured neuronal cells and the brain of targeted replacement mice. J Physiol Pharmacol 58(4):683–698PubMedGoogle Scholar
  21. Huebbe P, Nebel A, Siegert S, Moehring J, Boesch-Saadatmandi C, Most E, Pallauf J, Egert S, Muller MJ, Schreiber S, Nothlings U, Rimbach G (2011) APOE epsilon4 is associated with higher vitamin D levels in targeted replacement mice and humans. FASEB J 25(9):3262–3270. doi:10.1096/fj.11-180935 PubMedCrossRefGoogle Scholar
  22. Jiao Y, Wilkinson JT, Di X, Wang W, Hatcher H, Kock ND, D’Agostino R Jr, Knovich MA, Torti FM, Torti SV (2009) Curcumin, a cancer chemopreventive and chemotherapeutic agent, is a biologically active iron chelator. Blood 113(2):462–469. doi:10.1182/blood-2008-05-155952 PubMedCentralPubMedCrossRefGoogle Scholar
  23. Jofre-Monseny L, Minihane AM, Rimbach G (2008) Impact of apoE genotype on oxidative stress, inflammation and disease risk. Mol Nutr Food Res 52(1):131–145. doi:10.1002/mnfr.200700322 PubMedCrossRefGoogle Scholar
  24. Kamer AR, Craig RG, Pirraglia E, Dasanayake AP, Norman RG, Boylan RJ, Nehorayoff A, Glodzik L, Brys M, de Leon MJ (2009) TNF-alpha and antibodies to periodontal bacteria discriminate between Alzheimer’s disease patients and normal subjects. J Neuroimmunol 216(1–2):92–97. doi:10.1016/j.jneuroim.2009.08.013 PubMedCentralPubMedCrossRefGoogle Scholar
  25. Knouff C, Hinsdale ME, Mezdour H, Altenburg MK, Watanabe M, Quarfordt SH, Sullivan PM, Maeda N (1999) Apo E structure determines VLDL clearance and atherosclerosis risk in mice. J Clin Invest 103(11):1579–1586. doi:10.1172/JCI6172 PubMedCentralPubMedCrossRefGoogle Scholar
  26. Mattson MP, Cheng A (2006) Neurohormetic phytochemicals: low-dose toxins that induce adaptive neuronal stress responses. Trends Neurosci 29(11):632–639. doi:10.1016/j.tins.2006.09.001 PubMedCrossRefGoogle Scholar
  27. Ongwijitwat S, Liang HL, Graboyes EM, Wong-Riley MT (2006) Nuclear respiratory factor 2 senses changing cellular energy demands and its silencing down-regulates cytochrome oxidase and other target gene mRNAs. Gene 374:39–49. doi:http://www.ncbi.nlm.nih.gov/pubmed/16516409 PubMedCrossRefGoogle Scholar
  28. Puigserver P, Spiegelman BM (2003) Peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1 alpha): transcriptional coactivator and metabolic regulator. Endocr Rev 24(1):78–90PubMedCrossRefGoogle Scholar
  29. Puigserver P, Wu Z, Park CW, Graves R, Wright M, Spiegelman BM (1998) A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis. Cell 92(6):829–839PubMedCrossRefGoogle Scholar
  30. Ringman JM, Frautschy SA, Teng E, Begum AN, Bardens J, Beigi M, Gylys KH, Badmaev V, Heath DD, Apostolova LG, Porter V, Vanek Z, Marshall GA, Hellemann G, Sugar C, Masterman DL, Montine TJ, Cummings JL, Cole GM (2012) Oral curcumin for Alzheimer’s disease: tolerability and efficacy in a 24-week randomized, double blind, placebo-controlled study. Alzheimers Res Ther 4(5):43. doi:http://alzres.com/content/4/5/43 PubMedCentralPubMedCrossRefGoogle Scholar
  31. Rinwa P, Kaur B, Jaggi AS, Singh N (2010) Involvement of PPAR-gamma in curcumin-mediated beneficial effects in experimental dementia. Naunyn Schmiedebergs Arch Pharmacol 381(6):529–539. doi:10.1007/s00210-010-0511-z PubMedCrossRefGoogle Scholar
  32. Riviere GR, Riviere KH, Smith KS (2002) Molecular and immunological evidence of oral treponema in the human brain and their association with Alzheimer’s disease. Oral Microbiol Immunol 17(2):113–118. doi:http://www.ncbi.nlm.nih.gov/pubmed/11929559 PubMedCrossRefGoogle Scholar
  33. Schiborr C, Eckert GP, Rimbach G, Frank J (2010) A validated method for the quantification of curcumin in plasma and brain tissue by fast narrow-bore high-performance liquid chromatography with fluorescence detection. Anal Bioanal Chem 397(5):1917–1925. doi:10.1007/s00216-010-3719-3 PubMedCrossRefGoogle Scholar
  34. Sparks Stein P, Steffen MJ, Smith C, Jicha G, Ebersole JL, Abner E, Dawson D 3rd (2012) Serum antibodies to periodontal pathogens are a risk factor for Alzheimer’s disease. Alzheimers Dement 8(3):196–203. doi:10.1016/j.jalz.2011.04.006 PubMedCrossRefGoogle Scholar
  35. Stolzing A, Grune T (2003) Impairment of protein homeostasis and decline of proteasome activity in microglial cells from adult Wistar rats. J Neurosci Res 71(2):264–271. doi:10.1002/jnr.10478 PubMedCrossRefGoogle Scholar
  36. Strittmatter WJ, Roses AD (1996) Apolipoprotein E and Alzheimer’s disease. Annu Rev Neurosci 19:53–77. doi:10.1146/annurev.ne.19.030196.000413 PubMedCrossRefGoogle Scholar
  37. Sullivan PM, Mezdour H, Aratani Y, Knouff C, Najib J, Reddick RL, Quarfordt SH, Maeda N (1997) Targeted replacement of the mouse apolipoprotein E gene with the common human APOE3 allele enhances diet-induced hypercholesterolemia and atherosclerosis. J Biol Chem 272(29):17972–17980PubMedCrossRefGoogle Scholar
  38. Sullivan PM, Mezdour H, Quarfordt SH, Maeda N (1998) Type III hyperlipoproteinemia and spontaneous atherosclerosis in mice resulting from gene replacement of mouse Apoe with human Apoe*2. J Clin Invest 102(1):130–135. doi:10.1172/JCI2673 PubMedCentralPubMedCrossRefGoogle Scholar
  39. Tayler H, Fraser T, Miners JS, Kehoe PG, Love S (2010) Oxidative balance in Alzheimer’s disease: relationship to APOE, Braak tangle stage, and the concentrations of soluble and insoluble amyloid-beta. J Alzheimers Dis 22(4):1363–1373. doi:10.3233/JAD-2010-101368 PubMedGoogle Scholar
  40. Vitaglione P, Barone Lumaga R, Ferracane R, Radetsky I, Mennella I, Schettino R, Koder S, Shimoni E, Fogliano V (2012) Curcumin bioavailability from enriched bread: the effect of microencapsulated ingredients. J Agric Food Chem 60(13):3357–3366. doi:10.1021/jf204517k PubMedCrossRefGoogle Scholar
  41. Wang HM, Zhao YX, Zhang S, Liu GD, Kang WY, Tang HD, Ding JQ, Chen SD (2010) PPARgamma agonist curcumin reduces the amyloid-beta-stimulated inflammatory responses in primary astrocytes. J Alzheimers Dis 20(4):1189–1199. doi:10.3233/JAD-2010-091336 PubMedGoogle Scholar
  42. Wu Z, Puigserver P, Andersson U, Zhang C, Adelmant G, Mootha V, Troy A, Cinti S, Lowell B, Scarpulla RC, Spiegelman BM (1999) Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1. Cell 98(1):115–124. doi:10.1016/S0092-8674(00)80611-X PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Dawn Chin
    • 1
  • Stephanie Hagl
    • 2
  • Annika Hoehn
    • 3
  • Patricia Huebbe
    • 1
  • Kathrin Pallauf
    • 1
  • Tilman Grune
    • 3
  • Jan Frank
    • 4
  • Gunter P. Eckert
    • 2
  • Gerald Rimbach
    • 1
  1. 1.Institute of Human Nutrition and Food ScienceChristian-Albrechts-University KielKielGermany
  2. 2.Department of Pharmacology, Biocenter NiederurselUniversity of FrankfurtFrankfurtGermany
  3. 3.Institute of NutritionFriedrich Schiller University JenaJenaGermany
  4. 4.Institute of Biological Chemistry and NutritionUniversity of HohenheimStuttgartGermany

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