Skip to main content

Advertisement

SpringerLink
Log in

Mitochondrial DNA polymorphisms specifically modify cerebral β-amyloid proteostasis

  • Original Paper
  • Published:
Acta Neuropathologica Aims and scope Submit manuscript

Abstract

Several lines of evidence link mutations and deletions in mitochondrial DNA (mtDNA) and its maternal inheritance to neurodegenerative diseases in the elderly. Age-related mutations of mtDNA modulate the tricarboxylic cycle enzyme activity, mitochondrial oxidative phosphorylation capacity and oxidative stress response. To investigate the functional relevance of specific mtDNA polymorphisms of inbred mouse strains in the proteostasis regulation of the brain, we established novel mitochondrial congenic mouse lines of Alzheimer’s disease (AD). We crossed females from inbred strains (FVB/N, AKR/J, NOD/LtJ) with C57BL/6 males for at least ten generations to gain specific mitochondrial conplastic strains with pure C57BL/6 nuclear backgrounds. We show that specific mtDNA polymorphisms originating from the inbred strains differentially influence mitochondrial energy metabolism, ATP production and ATP-driven microglial activity, resulting in alterations of cerebral β-amyloid (Aβ) accumulation. Our findings demonstrate that mtDNA-related increases in ATP levels and subsequently in microglial activity are directly linked to decreased Aβ accumulation in vivo, implicating reduced mitochondrial function in microglia as a causative factor in the development of age-related cerebral proteopathies such as AD.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Avise JC, Lansman RA, Shade RO (1979) The use of restriction endonucleases to measure mitochondrial DNA sequence relatedness in natural populations. I. Population structure and evolution in the genus Peromyscus. Genetics 92(1):279–295

    PubMed  CAS  Google Scholar 

  2. Barrientos A, Fontanesi F, Diaz F (2009) Evaluation of the mitochondrial respiratory chain and oxidative phosphorylation system using polarography and spectrophotometric enzyme assays. In: Jonathan L Haines et al (eds) Current protocols in human genetics/editorial board. Chap 19:Unit 19.13

  3. Bateman RJ (2010) Amyloid-beta production and clearance rates in Alzheimer’s disease. Alzheimer’s Dementia 6(4):S101

    Article  Google Scholar 

  4. Chinnery PF, Taylor GA, Howell N, Brown DT, Parsons TJ, Turnbull DM (2001) Point mutations of the mtDNA control region in normal and neurodegenerative human brains. Am J Hum Genet 68(2):529–532

    Article  PubMed  CAS  Google Scholar 

  5. Coskun PE, Beal MF, Wallace DC (2004) Alzheimer’s brains harbor somatic mtDNA control-region mutations that suppress mitochondrial transcription and replication. Proc Natl Acad Sci USA 101(29):10726–10731

    Article  PubMed  CAS  Google Scholar 

  6. Cottrell DA, Turnbull DM (2000) Mitochondria and ageing. Curr Opin Clin Nutr Metab Care 3(6):473–478

    Article  PubMed  CAS  Google Scholar 

  7. Davalos D, Grutzendler J, Yang G, Kim JV, Zuo Y, Jung S, Littman DR, Dustin ML, Gan WB (2005) ATP mediates rapid microglial response to local brain injury in vivo. Nat Neurosci 8(6):752–758

    Article  PubMed  CAS  Google Scholar 

  8. Dibaj P, Nadrigny F, Steffens H, Scheller A, Hirrlinger J, Schomburg ED, Neusch C, Kirchhoff F (2010) NO mediates microglial response to acute spinal cord injury under ATP control in vivo. Glia 58(9):1133–1144

    Article  PubMed  Google Scholar 

  9. Eckert A, Hauptmann S, Scherping I, Meinhardt J, Rhein V, Drose S, Brandt U, Fandrich M, Muller WE, Gotz J (2008) Oligomeric and fibrillar species of beta-amyloid (A beta 42) both impair mitochondrial function in P301L tau transgenic mice. J Mol Med 86(11):1255–1267. doi:10.1007/s00109-008-0391-6

    Article  PubMed  CAS  Google Scholar 

  10. Eckert A, Schulz KL, Rhein V, Gotz J (2010) Convergence of amyloid-beta and tau pathologies on mitochondria in vivo. Mol Neurobiol 41(2–3):107–114. doi:10.1007/s12035-010-8109-5

    Article  PubMed  CAS  Google Scholar 

  11. Edgar D, Shabalina I, Camara Y, Wredenberg A, Calvaruso MA, Nijtmans L, Nedergaard J, Cannon B, Larsson NG, Trifunovic A (2009) Random point mutations with major effects on protein-coding genes are the driving force behind premature aging in mtDNA mutator mice. Cell Metab 10(2):131–138

    Article  PubMed  CAS  Google Scholar 

  12. Elson JL, Herrnstadt C, Preston G, Thal L, Morris CM, Edwardson JA, Beal MF, Turnbull DM, Howell N (2006) Does the mitochondrial genome play a role in the etiology of Alzheimer’s disease? Hum Genet 119(3):241–254

    Article  PubMed  CAS  Google Scholar 

  13. Grathwohl SA, Kalin RE, Bolmont T, Prokop S, Winkelmann G, Kaeser SA, Odenthal J, Radde R, Eldh T, Gandy S, Aguzzi A, Staufenbiel M, Mathews PM, Wolburg H, Heppner FL, Jucker M (2009) Formation and maintenance of Alzheimer’s disease beta-amyloid plaques in the absence of microglia. Nat Neurosci 12(11):1361–1363

    Article  PubMed  CAS  Google Scholar 

  14. Hanisch UK, Kettenmann H (2007) Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci 10(11):1387–1394

    Article  PubMed  CAS  Google Scholar 

  15. Horvath RJ, Nutile-McMenemy N, Alkaitis MS, Deleo JA (2008) Differential migration, LPS-induced cytokine, chemokine, and NO expression in immortalized BV-2 and HAPI cell lines and primary microglial cultures. J Neurochem 107(2):557–569

    Article  PubMed  CAS  Google Scholar 

  16. Jimenez S, Baglietto-Vargas D, Caballero C, Moreno-Gonzalez I, Torres M, Sanchez-Varo R, Ruano D, Vizuete M, Gutierrez A, Vitorica J (2008) Inflammatory response in the hippocampus of PS1M146L/APP751SL mouse model of Alzheimer’s disease: age-dependent switch in the microglial phenotype from alternative to classic. J Neurosci 28(45):11650–11661. doi:28/45/1165010.1523/JNEUROSCI.3024-08.2008

    Article  PubMed  CAS  Google Scholar 

  17. Johnson KR, Zheng QY, Bykhovskaya Y, Spirina O, Fischel-Ghodsian N (2001) A nuclear-mitochondrial DNA interaction affecting hearing impairment in mice. Nat Genet 27(2):191–194

    Article  PubMed  CAS  Google Scholar 

  18. Khan SM, Cassarino DS, Abramova NN, Keeney PM, Borland MK, Trimmer PA, Krebs CT, Bennett JC, Parks JK, Swerdlow RH, Parker WD Jr, Bennett JP Jr (2000) Alzheimer’s disease cybrids replicate beta-amyloid abnormalities through cell death pathways. Ann Neurol 48(2):148–155

    Article  PubMed  CAS  Google Scholar 

  19. Krauss S, Zhang CY, Lowell BB (2002) A significant portion of mitochondrial proton leak in intact thymocytes depends on expression of UCP2. Proc Natl Acad Sci USA 99(1):118–122. doi:10.1073/pnas012410699012410699

    Article  PubMed  CAS  Google Scholar 

  20. Krishnan KJ, Greaves LC, Reeve AK, Turnbull DM (2007) Mitochondrial DNA mutations and aging. Ann N Y Acad Sci 1100:227–240

    Article  PubMed  CAS  Google Scholar 

  21. Krohn M, Lange C, Hofrichter J, Scheffler K, Stenzel J, Steffen J, Schumacher T, Bruning T, Plath AS, Alfen F, Schmidt A, Winter F, Rateitschak K, Wree A, Gsponer J, Walker LC, Pahnke J (2011) Cerebral amyloid-beta proteostasis is regulated by the membrane transport protein ABCC1 in mice. J Clin Invest 121(10):3924–3931

    Article  PubMed  CAS  Google Scholar 

  22. Larsson NG (2010) Somatic mitochondrial DNA mutations in mammalian aging. Annu Rev Biochem 79:683–706

    Article  PubMed  CAS  Google Scholar 

  23. Lesné S, Koh MT, Kotilinek L, Kayed R, Glabe CG, Yang A, Gallagher M, Ashe KH (2006) A specific amyloid-beta protein assembly in the brain impairs memory. Nature 440(7082):352–357

    Article  PubMed  Google Scholar 

  24. Lin MT, Beal MF (2006) Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 443(7113):787–795

    Article  PubMed  CAS  Google Scholar 

  25. Mawuenyega KG, Sigurdson W, Ovod V, Munsell L, Kasten T, Morris JC, Yarasheski KE, Bateman RJ (2010) Decreased clearance of CNS beta-amyloid in Alzheimer’s disease. Science 330(6012):1774. doi:science.119762310.1126/science.1197623

    Article  PubMed  CAS  Google Scholar 

  26. Moreno-Loshuertos R, Acin-Perez R, Fernandez-Silva P, Movilla N, Perez-Martos A, Rodriguez de Cordoba S, Gallardo ME, Enriquez JA (2006) Differences in reactive oxygen species production explain the phenotypes associated with common mouse mitochondrial DNA variants. Nat Genet 38(11):1261–1268

    Article  PubMed  CAS  Google Scholar 

  27. Mosconi L, Berti V, Swerdlow RH, Pupi A, Duara R, de Leon M (2010) Maternal transmission of Alzheimer’s disease: prodromal metabolic phenotype and the search for genes. Hum Genomics 4(3):170–193 (pii:5T232214021U2841)

    Article  PubMed  CAS  Google Scholar 

  28. Perry VH, Nicoll JA, Holmes C (2010) Microglia in neurodegenerative disease. Nat Rev 6(4):193–201

    Google Scholar 

  29. Radde R, Bolmont T, Kaeser SA, Coomaraswamy J, Lindau D, Stoltze L, Calhoun ME, Jaggi F, Wolburg H, Gengler S, Haass C, Ghetti B, Czech C, Holscher C, Mathews PM, Jucker M (2006) Abeta42-driven cerebral amyloidosis in transgenic mice reveals early and robust pathology. EMBO Rep 7(9):940–946

    Article  PubMed  CAS  Google Scholar 

  30. Roubertoux PL, Sluyter F, Carlier M, Marcet B, Maarouf-Veray F, Cherif C, Marican C, Arrechi P, Godin F, Jamon M, Verrier B, Cohen-Salmon C (2003) Mitochondrial DNA modifies cognition in interaction with the nuclear genome and age in mice. Nat Genet 35(1):65–69

    Article  PubMed  CAS  Google Scholar 

  31. Scheffler K, Stenzel J, Krohn M, Lange C, Hofrichter J, Schumacher T, Bruning T, Plath AS, Walker L, Pahnke J (2011) Determination of spatial and temporal distribution of microglia by 230 nm-high-resolution, high-throughput automated analysis reveals different amyloid plaque populations in an APP/PS1 mouse model of Alzheimer’s disease. Curr Alzheimer Res 8(7):781–788. doi:BSP/CAR/0134

    Article  PubMed  CAS  Google Scholar 

  32. Smits P, Mattijssen S, Morava E, van den Brand M, van den Brandt F, Wijburg F, Pruijn G, Smeitink J, Nijtmans L, Rodenburg R, van den Heuvel L (2010) Functional consequences of mitochondrial tRNA Trp and tRNA Arg mutations causing combined OXPHOS defects. Eur J Hum Genet 18(3):324–329

    Article  PubMed  CAS  Google Scholar 

  33. Swerdlow RH, Parks JK, Cassarino DS, Maguire DJ, Maguire RS, Bennett JP Jr, Davis RE, Parker WD Jr (1997) Cybrids in Alzheimer’s disease: a cellular model of the disease? Neurology 49(4):918–925

    Article  PubMed  CAS  Google Scholar 

  34. Tanaka N, Goto Y, Akanuma J, Kato M, Kinoshita T, Yamashita F, Tanaka M, Asada T (2010) Mitochondrial DNA variants in a Japanese population of patients with Alzheimer’s disease. Mitochondrion 10(1):32–37

    Article  PubMed  CAS  Google Scholar 

  35. Wallace DC (1999) Mitochondrial diseases in man and mouse. Science 283(5407):1482–1488

    Article  PubMed  CAS  Google Scholar 

  36. Wallace DC, Fan W (2009) The pathophysiology of mitochondrial disease as modeled in the mouse. Genes Dev 23(15):1714–1736

    Article  PubMed  CAS  Google Scholar 

  37. Wang PN, Lee HC, Wang CH, Ping YH, Liu TY, Chi CW, Lin KN, Liu HC (2009) Heteroplasmy of mitochondrial D310 mononucleotide repeat region in the blood of patients with Alzheimer’s disease. J Alzheimers Dis 18(2):345–353

    PubMed  CAS  Google Scholar 

  38. Yu X, Wester-Rosenlof L, Gimsa U, Holzhueter SA, Marques A, Jonas L, Hagenow K, Kunz M, Nizze H, Tiedge M, Holmdahl R, Ibrahim SM (2009) The mtDNA nt7778 G/T polymorphism affects autoimmune diseases and reproductive performance in the mouse. Hum Mol Genet 18(24):4689–4698

    Article  PubMed  CAS  Google Scholar 

  39. Zhang CY, Baffy G, Perret P, Krauss S, Peroni O, Grujic D, Hagen T, Vidal-Puig AJ, Boss O, Kim YB, Zheng XX, Wheeler MB, Shulman GI, Chan CB, Lowell BB (2001) Uncoupling protein-2 negatively regulates insulin secretion and is a major link between obesity, beta cell dysfunction, and type 2 diabetes. Cell 105(6):745–755

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors thanks K. Nakamura and J. Götz for comments on the manuscript, and Thomas Brüning, Anne-Sophie Plath and Franziska Alfen for technical support. This work was supported by grants from the county of Mecklenburg-Western Pomerania (LGF funding to K.S. and J.S., Excellence Initiative 69027037/290100/2010—UR 09 020 to J.P.), INF Rostock (to M.K.), NIH (RR-00165) and the CART Foundation (to L.C.W.) and the German Science Foundation (DFG ExC 306/1, to S.I.).

Conflict of interest

The authors declare that they have no competing financial interests.

Author information

Author notes

  1. Katja Scheffler

    Present address: Department of Biochemistry, University of Oslo, Oslo, Norway

Authors and Affiliations

  1. Department of Neurology, Neurodegeneration Research Laboratory (NRL), Universities of Rostock, Rostock, Germany

    Katja Scheffler, Markus Krohn, Tina Dunkelmann, Jan Stenzel, Hans-Jochen Heinze & Jens Pahnke

  2. German Centre for Neurodegenerative Diseases (DZNE), Magdeburg, Germany

    Markus Krohn & Jens Pahnke

  3. Laboratoire de Biologie Physico-Chimique des Protéines Membranaires, UMR 7099, Institut de Biologie Physico-Chimique, Paris, France

    Bruno Miroux

  4. Department of Dermatology, University of Lübeck, Lubeck, Germany

    Saleh Ibrahim

  5. Institute of Anatomy, University of Greifswald, Greifswald, Germany

    Oliver von Bohlen und Halbach

  6. Leibniz Institute for Neurobiology, Magdeburg, Germany

    Hans-Jochen Heinze & Jens Pahnke

  7. Yerkes National Primate Research Center and Department of Neurology, Emory University, Atlanta, GA, USA

    Lary C. Walker

  8. Center for High-Throughput Biology, University of British Columbia, Vancouver, Canada

    Jörg A. Gsponer

  9. Department of Neurology, Neurodegeneration Research Laboratory (NRL), Universities of Magdeburg, Leipziger Str. 44, H15, 39120, Magdeburg, Germany

    Jens Pahnke

Authors
  1. Katja Scheffler
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Markus Krohn
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tina Dunkelmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jan Stenzel
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Bruno Miroux
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Saleh Ibrahim
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Oliver von Bohlen und Halbach
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Hans-Jochen Heinze
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Lary C. Walker
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Jörg A. Gsponer
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Jens Pahnke
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jens Pahnke.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 702 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Scheffler, K., Krohn, M., Dunkelmann, T. et al. Mitochondrial DNA polymorphisms specifically modify cerebral β-amyloid proteostasis. Acta Neuropathol 124, 199–208 (2012). https://doi.org/10.1007/s00401-012-0980-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00401-012-0980-x

Keywords

Search

Navigation