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Aβ25–35 Suppresses Mitochondrial Biogenesis in Primary Hippocampal Neurons

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Abstract

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.

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References

  • 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 31:316–326

    Article  PubMed  CAS  Google Scholar 

  • 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 22:1056–1085

    Article  CAS  Google Scholar 

  • 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 40:365–373

    Article  PubMed  CAS  Google Scholar 

  • 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 20:4515–4529

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Canevari L, Clark JB, Bates TE (1999) beta-Amyloid fragment 25-35 selectively decreases complex IV activity in isolated mitochondria. FEBS Lett 457:131–134

    Article  PubMed  CAS  Google Scholar 

  • 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 458:1056–1060

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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 10:258–267

    Article  PubMed  CAS  Google Scholar 

  • 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 9:420

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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:e34929

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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 107:12553–12558

    Article  PubMed  PubMed Central  Google Scholar 

  • Chen JX, Yan SD (2007) Amyloid-beta-induced mitochondrial dysfunction. J Alzheimers Dis 12:177–184

    PubMed  PubMed Central  CAS  Google Scholar 

  • 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 26:6011–6018

    Article  PubMed  CAS  Google Scholar 

  • 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 48:117–125

    Article  PubMed  CAS  Google Scholar 

  • 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 13:64

    Article  PubMed  PubMed Central  Google Scholar 

  • 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 14:1097–1105

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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 29:895–900

    Article  PubMed  CAS  Google Scholar 

  • Fulco M, Sartorelli V (2008) Comparing and contrasting the roles of AMPK and SIRT1 in metabolic tissues. Cell Cycle 7:3669–3679

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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 14:661–673

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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 26:1913–1923

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Hardie DG (2007) AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy. Nat Rev Mol Cell Biol 8:774–785

    Article  PubMed  CAS  Google Scholar 

  • Hardy J, Selkoe DJ (2002) The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 297:353–356

    Article  PubMed  CAS  Google Scholar 

  • Ittner LM, Gotz J (2010) Amyloid-beta and tau—a toxic pas de deux in Alzheimer’s disease. Nat Rev Neurosci 12:65–72

    Article  PubMed  CAS  Google Scholar 

  • 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 104:12017–12022

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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–E1239

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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 68:48–58

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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 221:26–37

    Article  PubMed  CAS  Google Scholar 

  • 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 26:3169–3179

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Kwon HS, Ott M (2008) The ups and downs of SIRT1. Trends Biochem Sci 33:517–525

    Article  PubMed  CAS  Google Scholar 

  • 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 60:157–167

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Lin J, Handschin C, Spiegelman BM (2005) Metabolic control through the PGC-1 family of transcription coactivators. Cell Metab 1:361–370

    Article  PubMed  CAS  Google Scholar 

  • Liu CT, Brooks GA (2012) Mild heat stress induces mitochondrial biogenesis in C2C12 myotubes. J Appl Physiol (1985) 112:354–361

    Article  CAS  Google Scholar 

  • 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:e606

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65:55–63

    Article  PubMed  CAS  Google Scholar 

  • Nemoto S, Fergusson MM, Finkel T (2005) SIRT1 functionally interacts with the metabolic regulator and transcriptional coactivator PGC-1{alpha}. J Biol Chem 280:16456–16460

    Article  PubMed  Google Scholar 

  • 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 32:14311–14317

    Article  PubMed  CAS  Google Scholar 

  • 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 1842:1556–1566

    Article  PubMed  CAS  Google Scholar 

  • 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 300:1140–1142

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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 13:1676–1687

    PubMed  CAS  Google Scholar 

  • 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 15:675–690

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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 66:352–361

    Article  PubMed  PubMed Central  Google Scholar 

  • 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 1143:11–21

    Article  PubMed  CAS  Google Scholar 

  • 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 40:319–330

    PubMed  CAS  Google Scholar 

  • 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 434:113–118

    Article  PubMed  CAS  Google Scholar 

  • 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 104:7933–7938

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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–E760

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Scarpulla RC (2011) Metabolic control of mitochondrial biogenesis through the PGC-1 family regulatory network. Biochim Biophys Acta 1813:1269–1278

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Selkoe DJ (2004) Cell biology of protein misfolding: the examples of Alzheimer’s and Parkinson’s diseases. Nat Cell Biol 6:1054–1061

    Article  PubMed  CAS  Google Scholar 

  • 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 16:175–190

    Article  PubMed  CAS  Google Scholar 

  • 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 120:419–429

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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 76:884–895

    Article  PubMed  CAS  Google Scholar 

  • 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 447:485–489

    Article  PubMed  CAS  Google Scholar 

  • 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 29:860–868

    Article  PubMed  CAS  Google Scholar 

  • 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 20:1868–1876

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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 91:1309–1313

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Wang L, Brautigan DL (2013) alpha-SNAP inhibits AMPK signaling to reduce mitochondrial biogenesis and dephosphorylates Thr172 in AMPKalpha in vitro. Nat Commun 4:1559

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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 1842:1240–1247

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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 20:1111–1121

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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 98:115–124

    Article  PubMed  CAS  Google Scholar 

  • 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 33:17042–17051

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Yankner BA, Duffy LK, Kirschner DA (1990) Neurotrophic and neurotoxic effects of amyloid beta protein: reversal by tachykinin neuropeptides. Science 250:279–282

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

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.

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

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Authors and Affiliations

  1. Department of Integrated Traditional Chinese and Western Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, 350122, Fujian, People’s Republic of China

    Weiguo Dong, Feng Wang, Xuehua Zheng, Yue Chen, Wenguang Zhang & Hong Shi

  2. The Third People’s Hospital of Fujian Province, Fuzhou, 350122, Fujian, People’s Republic of China

    Wanqing Guo

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  1. Weiguo Dong
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  2. Feng Wang
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Correspondence to Weiguo Dong.

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Dong, W., Wang, F., Guo, W. et al. Aβ25–35 Suppresses Mitochondrial Biogenesis in Primary Hippocampal Neurons. Cell Mol Neurobiol 36, 83–91 (2016). https://doi.org/10.1007/s10571-015-0222-6

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