Acta Neuropathologica

, Volume 124, Issue 2, pp 199–208 | Cite as

Mitochondrial DNA polymorphisms specifically modify cerebral β-amyloid proteostasis

  • Katja Scheffler
  • Markus Krohn
  • Tina Dunkelmann
  • Jan Stenzel
  • Bruno Miroux
  • Saleh Ibrahim
  • Oliver von Bohlen und Halbach
  • Hans-Jochen Heinze
  • Lary C. Walker
  • Jörg A. Gsponer
  • Jens PahnkeEmail author
Original Paper


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.


Abeta Mitochondrial congenic mice Conplastic Alzheimer’s disease Amyloid-beta Microglia Mitochondria 



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.

Supplementary material

401_2012_980_MOESM1_ESM.pdf (703 kb)
Supplementary material 1 (PDF 702 kb)


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Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Katja Scheffler
    • 1
    • 9
  • Markus Krohn
    • 1
    • 2
  • Tina Dunkelmann
    • 1
  • Jan Stenzel
    • 1
  • Bruno Miroux
    • 3
  • Saleh Ibrahim
    • 4
  • Oliver von Bohlen und Halbach
    • 5
  • Hans-Jochen Heinze
    • 1
    • 6
  • Lary C. Walker
    • 7
  • Jörg A. Gsponer
    • 8
  • Jens Pahnke
    • 1
    • 2
    • 6
    • 10
    Email author
  1. 1.Department of Neurology, Neurodegeneration Research Laboratory (NRL)Universities of RostockRostockGermany
  2. 2.German Centre for Neurodegenerative Diseases (DZNE)MagdeburgGermany
  3. 3.Laboratoire de Biologie Physico-Chimique des Protéines Membranaires, UMR 7099Institut de Biologie Physico-ChimiqueParisFrance
  4. 4.Department of DermatologyUniversity of LübeckLubeckGermany
  5. 5.Institute of AnatomyUniversity of GreifswaldGreifswaldGermany
  6. 6.Leibniz Institute for NeurobiologyMagdeburgGermany
  7. 7.Yerkes National Primate Research Center and Department of NeurologyEmory UniversityAtlantaUSA
  8. 8.Center for High-Throughput BiologyUniversity of British ColumbiaVancouverCanada
  9. 9.Department of BiochemistryUniversity of OsloOsloNorway
  10. 10.Department of Neurology, Neurodegeneration Research Laboratory (NRL)Universities of MagdeburgMagdeburgGermany

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