Cellular and Molecular Neurobiology

, Volume 36, Issue 1, pp 83–91 | Cite as

Aβ25–35 Suppresses Mitochondrial Biogenesis in Primary Hippocampal Neurons

  • Weiguo Dong
  • Feng Wang
  • Wanqing Guo
  • Xuehua Zheng
  • Yue Chen
  • Wenguang Zhang
  • Hong Shi
Original Research


Mitochondrial biogenesis is involved in the regulation of mitochondrial content, morphology, and function. Impaired mitochondrial biogenesis has been observed in Alzheimer’s disease. Amyloid-β (Aβ) has been shown to cause mitochondrial dysfunction in cultured neurons, but its role in mitochondrial biogenesis in neurons remains poorly defined. AMP-activated protein kinase (AMPK) and sirtuin 1 (SIRT1) are key energy-sensing molecules regulating mitochondrial biogenesis. In addition, peroxisome proliferator-activated receptor-γ coactivator 1-alpha (PGC-1α), the master regulator of mitochondrial biogenesis, is a target for SIRT1 deacetylase activity. In this study, we investigated the effects of Aβ25–35 on mitochondrial biogenesis in cultured hippocampal neurons and the underlying mechanisms. In primary hippocampal neurons, we found that 24-h incubation with Aβ25–35 suppressed both phosphorylations of AMPK and SIRT1 expression and increased PGC-1α acetylation expression. In addition, Aβ25–35 also resulted in a decrease in mitochondrial DNA copy number, as well as decreases in the expression of mitochondrial biogenesis factors (PGC-1α, NRF 1, NRF 2, and Tfam). Taken together, these data show that Aβ25–35 suppresses mitochondrial biogenesis in hippocampal neurons. Aβ25–35-induced impairment of mitochondrial biogenesis may be associated with the inhibition of the AMPK-SIRT1-PGC-1α pathway.


Alzheimer’s disease Mitochondrial biogenesis Amyloid-β AMPK SIRT1 PGC-1α 



This work was supported by the National Natural Science Foundation of China (Project 81102625), the Natural Science Foundation of Fujian Province Grants (Project 2012J05154), and study abroad scholarships of Fujian Province.

Conflict of interest

The authors declare no financial or other conflicts of interest related to this study.


  1. Arancibia S, Silhol M, Mouliere F, Meffre J, Hollinger I, Maurice T, Tapia-Arancibia L (2008) Protective effect of BDNF against beta-amyloid induced neurotoxicity in vitro and in vivo in rats. Neurobiol Dis 31:316–326PubMedCrossRefGoogle Scholar
  2. Benek O, Aitken L, Hroch L, Kuca K, Gunn-Moore F, Musilek K (2015) A direct interaction between mitochondrial proteins and amyloid-beta peptide and its significance for the progression and treatment of Alzheimer`s disease. Curr Med Chem 22:1056–1085CrossRefGoogle Scholar
  3. Bulbarelli A, Lonati E, Cazzaniga E, Re F, Sesana S, Barisani D, Sancini G, Mutoh T, Masserini M (2009) TrkA pathway activation induced by amyloid-beta (Abeta). Mol Cell Neurosci 40:365–373PubMedCrossRefGoogle Scholar
  4. Calkins MJ, Manczak M, Mao P, Shirendeb U, Reddy PH (2011) Impaired mitochondrial biogenesis, defective axonal transport of mitochondria, abnormal mitochondrial dynamics and synaptic degeneration in a mouse model of Alzheimer’s disease. Hum Mol Genet 20:4515–4529PubMedPubMedCentralCrossRefGoogle Scholar
  5. Canevari L, Clark JB, Bates TE (1999) beta-Amyloid fragment 25-35 selectively decreases complex IV activity in isolated mitochondria. FEBS Lett 457:131–134PubMedCrossRefGoogle Scholar
  6. Canto C, Gerhart-Hines Z, Feige JN, Lagouge M, Noriega L, Milne JC, Elliott PJ, Puigserver P, Auwerx J (2009) AMPK regulates energy expenditure by modulating NAD + metabolism and SIRT1 activity. Nature 458:1056–1060PubMedPubMedCentralCrossRefGoogle Scholar
  7. Casley CS, Land JM, Sharpe MA, Clark JB, Duchen MR, Canevari L (2002) Beta-amyloid fragment 25-35 causes mitochondrial dysfunction in primary cortical neurons. Neurobiol Dis 10:258–267PubMedCrossRefGoogle Scholar
  8. Casuso RA, Martinez-Lopez EJ, Hita-Contreras F, Camiletti-Moiron D, Martinez-Romero R, Canuelo A, Martinez-Amat A (2014) The combination of oral quercetin supplementation and exercise prevents brain mitochondrial biogenesis. Genes Nutr 9:420PubMedPubMedCentralCrossRefGoogle Scholar
  9. Cha MY, Han SH, Son SM, Hong HS, Choi YJ, Byun J, Mook-Jung I (2012) Mitochondria-specific accumulation of amyloid beta induces mitochondrial dysfunction leading to apoptotic cell death. PLoS One 7:e34929PubMedPubMedCentralCrossRefGoogle Scholar
  10. Chau MD, Gao J, Yang Q, Wu Z, Gromada J (2010) Fibroblast growth factor 21 regulates energy metabolism by activating the AMPK-SIRT1-PGC-1alpha pathway. Proc Natl Acad Sci USA 107:12553–12558PubMedPubMedCentralCrossRefGoogle Scholar
  11. Chen JX, Yan SD (2007) Amyloid-beta-induced mitochondrial dysfunction. J Alzheimers Dis 12:177–184PubMedPubMedCentralGoogle Scholar
  12. Deshpande A, Mina E, Glabe C, Busciglio J (2006) Different conformations of amyloid beta induce neurotoxicity by distinct mechanisms in human cortical neurons. J Neurosci 26:6011–6018PubMedCrossRefGoogle Scholar
  13. Dong W, Huang F, Fan W, Cheng S, Chen Y, Zhang W, Shi H, He H (2010) Differential effects of melatonin on amyloid-beta peptide 25-35-induced mitochondrial dysfunction in hippocampal neurons at different stages of culture. J Pineal Res 48:117–125PubMedCrossRefGoogle Scholar
  14. Dong GZ, Jang EJ, Kang SH, Cho IJ, Park SD, Kim SC, Kim YW (2013) Red ginseng abrogates oxidative stress via mitochondria protection mediated by LKB1-AMPK pathway. BMC Complement Altern Med 13:64PubMedPubMedCentralCrossRefGoogle Scholar
  15. Du H, Guo L, Fang F, Chen D, Sosunov AA, McKhann GM, Yan Y, Wang C, Zhang H, Molkentin JD, Gunn-Moore FJ, Vonsattel JP, Arancio O, Chen JX, Yan SD (2008) Cyclophilin D deficiency attenuates mitochondrial and neuronal perturbation and ameliorates learning and memory in Alzheimer’s disease. Nat Med 14:1097–1105PubMedPubMedCentralCrossRefGoogle Scholar
  16. Filipcik P, Cente M, Krajciova G, Vanicky I, Novak M (2009) Cortical and hippocampal neurons from truncated tau transgenic rat express multiple markers of neurodegeneration. Cell Mol Neurobiol 29:895–900PubMedCrossRefGoogle Scholar
  17. Fulco M, Sartorelli V (2008) Comparing and contrasting the roles of AMPK and SIRT1 in metabolic tissues. Cell Cycle 7:3669–3679PubMedPubMedCentralCrossRefGoogle Scholar
  18. Fulco M, Cen Y, Zhao P, Hoffman EP, McBurney MW, Sauve AA, Sartorelli V (2008) Glucose restriction inhibits skeletal myoblast differentiation by activating SIRT1 through AMPK-mediated regulation of Nampt. Dev Cell 14:661–673PubMedPubMedCentralCrossRefGoogle Scholar
  19. Gerhart-Hines Z, Rodgers JT, Bare O, Lerin C, Kim SH, Mostoslavsky R, Alt FW, Wu Z, Puigserver P (2007) Metabolic control of muscle mitochondrial function and fatty acid oxidation through SIRT1/PGC-1alpha. EMBO J 26:1913–1923PubMedPubMedCentralCrossRefGoogle Scholar
  20. Hardie DG (2007) AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy. Nat Rev Mol Cell Biol 8:774–785PubMedCrossRefGoogle Scholar
  21. Hardy J, Selkoe DJ (2002) The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 297:353–356PubMedCrossRefGoogle Scholar
  22. Ittner LM, Gotz J (2010) Amyloid-beta and tau—a toxic pas de deux in Alzheimer’s disease. Nat Rev Neurosci 12:65–72PubMedCrossRefGoogle Scholar
  23. Jager S, Handschin C, St-Pierre J, Spiegelman BM (2007) AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1alpha. Proc Natl Acad Sci USA 104:12017–12022PubMedPubMedCentralCrossRefGoogle Scholar
  24. Joshi G, Chi Y, Huang Z, Wang Y (2014) Abeta-induced Golgi fragmentation in Alzheimer’s disease enhances Abeta production. Proc Natl Acad Sci USA 111:E1230–E1239PubMedPubMedCentralCrossRefGoogle Scholar
  25. Julien C, Tremblay C, Emond V, Lebbadi M, Salem N Jr, Bennett DA, Calon F (2009) Sirtuin 1 reduction parallels the accumulation of tau in Alzheimer disease. J Neuropathol Exp Neurol 68:48–58PubMedPubMedCentralCrossRefGoogle Scholar
  26. Kaminsky YG, Marlatt MW, Smith MA, Kosenko EA (2010) Subcellular and metabolic examination of amyloid-beta peptides in Alzheimer disease pathogenesis: evidence for Abeta(25-35). Exp Neurol 221:26–37PubMedCrossRefGoogle Scholar
  27. Kim D, Nguyen MD, Dobbin MM, Fischer A, Sananbenesi F, Rodgers JT, Delalle I, Baur JA, Sui G, Armour SM, Puigserver P, Sinclair DA, Tsai LH (2007) SIRT1 deacetylase protects against neurodegeneration in models for Alzheimer’s disease and amyotrophic lateral sclerosis. EMBO J 26:3169–3179PubMedPubMedCentralCrossRefGoogle Scholar
  28. Kwon HS, Ott M (2008) The ups and downs of SIRT1. Trends Biochem Sci 33:517–525PubMedCrossRefGoogle Scholar
  29. Li L, Pan R, Li R, Niemann B, Aurich AC, Chen Y, Rohrbach S (2011) Mitochondrial biogenesis and peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) deacetylation by physical activity: intact adipocytokine signaling is required. Diabetes 60:157–167PubMedPubMedCentralCrossRefGoogle Scholar
  30. Lin J, Handschin C, Spiegelman BM (2005) Metabolic control through the PGC-1 family of transcription coactivators. Cell Metab 1:361–370PubMedCrossRefGoogle Scholar
  31. Liu CT, Brooks GA (2012) Mild heat stress induces mitochondrial biogenesis in C2C12 myotubes. J Appl Physiol (1985) 112:354–361CrossRefGoogle Scholar
  32. Moran C, Sanz-Rodriguez A, Jimenez-Pacheco A, Martinez-Villareal J, McKiernan RC, Jimenez-Mateos EM, Mooney C, Woods I, Prehn JH, Henshall DC, Engel T (2013) Bmf upregulation through the AMP-activated protein kinase pathway may protect the brain from seizure-induced cell death. Cell Death Dis 4:e606PubMedPubMedCentralCrossRefGoogle Scholar
  33. Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65:55–63PubMedCrossRefGoogle Scholar
  34. Nemoto S, Fergusson MM, Finkel T (2005) SIRT1 functionally interacts with the metabolic regulator and transcriptional coactivator PGC-1{alpha}. J Biol Chem 280:16456–16460PubMedCrossRefGoogle Scholar
  35. Ng CH, Guan MS, Koh C, Ouyang X, Yu F, Tan EK, O’Neill SP, Zhang X, Chung J, Lim KL (2012) AMP kinase activation mitigates dopaminergic dysfunction and mitochondrial abnormalities in Drosophila models of Parkinson’s disease. J Neurosci 32:14311–14317PubMedCrossRefGoogle Scholar
  36. Pedros I, Petrov D, Allgaier M, Sureda F, Barroso E, Beas-Zarate C, Auladell C, Pallas M, Vazquez-Carrera M, Casadesus G, Folch J, Camins A (2014) Early alterations in energy metabolism in the hippocampus of APPswe/PS1dE9 mouse model of Alzheimer’s disease. Biochim Biophys Acta 1842:1556–1566PubMedCrossRefGoogle Scholar
  37. Petersen KF, Befroy D, Dufour S, Dziura J, Ariyan C, Rothman DL, DiPietro L, Cline GW, Shulman GI (2003) Mitochondrial dysfunction in the elderly: possible role in insulin resistance. Science 300:1140–1142PubMedPubMedCentralCrossRefGoogle Scholar
  38. Pike CJ, Burdick D, Walencewicz AJ, Glabe CG, Cotman CW (1993) Neurodegeneration induced by beta-amyloid peptides in vitro: the role of peptide assembly state. J Neurosci 13:1676–1687PubMedGoogle Scholar
  39. Price NL, Gomes AP, Ling AJ, Duarte FV, Martin-Montalvo A, North BJ, Agarwal B, Ye L, Ramadori G, Teodoro JS, Hubbard BP, Varela AT, Davis JG, Varamini B, Hafner A, Moaddel R, Rolo AP, Coppari R, Palmeira CM, de Cabo R, Baur JA, Sinclair DA (2012) SIRT1 is required for AMPK activation and the beneficial effects of resveratrol on mitochondrial function. Cell Metab 15:675–690PubMedPubMedCentralCrossRefGoogle Scholar
  40. Qin W, Haroutunian V, Katsel P, Cardozo CP, Ho L, Buxbaum JD, Pasinetti GM (2009) PGC-1alpha expression decreases in the Alzheimer disease brain as a function of dementia. Arch Neurol 66:352–361PubMedPubMedCentralCrossRefGoogle Scholar
  41. Resende R, Pereira C, Agostinho P, Vieira AP, Malva JO, Oliveira CR (2007) Susceptibility of hippocampal neurons to Abeta peptide toxicity is associated with perturbation of Ca2+ homeostasis. Brain Res 1143:11–21PubMedCrossRefGoogle Scholar
  42. Rice AC, Keeney PM, Algarzae NK, Ladd AC, Thomas RR, Bennett JP Jr (2014) Mitochondrial DNA copy numbers in pyramidal neurons are decreased and mitochondrial biogenesis transcriptome signaling is disrupted in Alzheimer’s disease hippocampi. J Alzheimers Dis 40:319–330PubMedGoogle Scholar
  43. Rodgers JT, Lerin C, Haas W, Gygi SP, Spiegelman BM, Puigserver P (2005) Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1. Nature 434:113–118PubMedCrossRefGoogle Scholar
  44. Rohas LM, St-Pierre J, Uldry M, Jager S, Handschin C, Spiegelman BM (2007) A fundamental system of cellular energy homeostasis regulated by PGC-1alpha. Proc Natl Acad Sci USA 104:7933–7938PubMedPubMedCentralCrossRefGoogle Scholar
  45. Ruderman NB, Xu XJ, Nelson L, Cacicedo JM, Saha AK, Lan F, Ido Y (2010) AMPK and SIRT1: a long-standing partnership? Am J Physiol Endocrinol Metab 298:E751–E760PubMedPubMedCentralCrossRefGoogle Scholar
  46. Scarpulla RC (2011) Metabolic control of mitochondrial biogenesis through the PGC-1 family regulatory network. Biochim Biophys Acta 1813:1269–1278PubMedPubMedCentralCrossRefGoogle Scholar
  47. Selkoe DJ (2004) Cell biology of protein misfolding: the examples of Alzheimer’s and Parkinson’s diseases. Nat Cell Biol 6:1054–1061PubMedCrossRefGoogle Scholar
  48. Shaerzadeh F, Motamedi F, Minai-Tehrani D, Khodagholi F (2014) Monitoring of neuronal loss in the hippocampus of Abeta-injected rat: autophagy, mitophagy, and mitochondrial biogenesis stand against apoptosis. Neuromolecular Med 16:175–190PubMedCrossRefGoogle Scholar
  49. Sheng B, Wang X, Su B, Lee HG, Casadesus G, Perry G, Zhu X (2012) Impaired mitochondrial biogenesis contributes to mitochondrial dysfunction in Alzheimer’s disease. J Neurochem 120:419–429PubMedPubMedCentralCrossRefGoogle Scholar
  50. Shin SM, Cho IJ, Kim SG (2009) Resveratrol protects mitochondria against oxidative stress through AMP-activated protein kinase-mediated glycogen synthase kinase-3beta inhibition downstream of poly(ADP-ribose)polymerase-LKB1 pathway. Mol Pharmacol 76:884–895PubMedCrossRefGoogle Scholar
  51. Sun Q, Hu H, Wang W, Jin H, Feng G, Jia N (2014) Taurine attenuates amyloid beta 1-42-induced mitochondrial dysfunction by activating of SIRT1 in SK-N-SH cells. Biochem Biophys Res Commun 447:485–489PubMedCrossRefGoogle Scholar
  52. Tohda C, Matsumoto N, Zou K, Meselhy MR, Komatsu K (2004) Abeta(25-35)-induced memory impairment, axonal atrophy, and synaptic loss are ameliorated by M1, A metabolite of protopanaxadiol-type saponins. Neuropsychopharmacology 29:860–868PubMedCrossRefGoogle Scholar
  53. Vega RB, Huss JM, Kelly DP (2000) The coactivator PGC-1 cooperates with peroxisome proliferator-activated receptor alpha in transcriptional control of nuclear genes encoding mitochondrial fatty acid oxidation enzymes. Mol Cell Biol 20:1868–1876PubMedPubMedCentralCrossRefGoogle Scholar
  54. Virbasius JV, Scarpulla RC (1994) Activation of the human mitochondrial transcription factor A gene by nuclear respiratory factors: a potential regulatory link between nuclear and mitochondrial gene expression in organelle biogenesis. Proc Natl Acad Sci USA 91:1309–1313PubMedPubMedCentralCrossRefGoogle Scholar
  55. Wang L, Brautigan DL (2013) alpha-SNAP inhibits AMPK signaling to reduce mitochondrial biogenesis and dephosphorylates Thr172 in AMPKalpha in vitro. Nat Commun 4:1559PubMedPubMedCentralCrossRefGoogle Scholar
  56. Wang X, Wang W, Li L, Perry G, Lee HG, Zhu X (2014) Oxidative stress and mitochondrial dysfunction in Alzheimer’s disease. Biochim Biophys Acta 1842:1240–1247PubMedPubMedCentralCrossRefGoogle Scholar
  57. Wei H, Zhang Z, Saha A, Peng S, Chandra G, Quezado Z, Mukherjee AB (2011) Disruption of adaptive energy metabolism and elevated ribosomal p-S6K1 levels contribute to INCL pathogenesis: partial rescue by resveratrol. Hum Mol Genet 20:1111–1121PubMedPubMedCentralCrossRefGoogle Scholar
  58. 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 98:115–124PubMedCrossRefGoogle Scholar
  59. Xie H, Guan J, Borrelli LA, Xu J, Serrano-Pozo A, Bacskai BJ (2013) Mitochondrial alterations near amyloid plaques in an Alzheimer’s disease mouse model. J Neurosci 33:17042–17051PubMedPubMedCentralCrossRefGoogle Scholar
  60. Yankner BA, Duffy LK, Kirschner DA (1990) Neurotrophic and neurotoxic effects of amyloid beta protein: reversal by tachykinin neuropeptides. Science 250:279–282PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Weiguo Dong
    • 1
  • Feng Wang
    • 1
  • Wanqing Guo
    • 2
  • Xuehua Zheng
    • 1
  • Yue Chen
    • 1
  • Wenguang Zhang
    • 1
  • Hong Shi
    • 1
  1. 1.Department of Integrated Traditional Chinese and Western MedicineFujian University of Traditional Chinese MedicineFuzhouPeople’s Republic of China
  2. 2.The Third People’s Hospital of Fujian ProvinceFuzhouPeople’s Republic of China

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