Acta Neuropathologica

, Volume 124, Issue 2, pp 199–208

Mitochondrial DNA polymorphisms specifically modify cerebral β-amyloid proteostasis

Authors

  • Katja Scheffler
    • Department of Neurology, Neurodegeneration Research Laboratory (NRL)Universities of Rostock
    • Department of BiochemistryUniversity of Oslo
  • Markus Krohn
    • Department of Neurology, Neurodegeneration Research Laboratory (NRL)Universities of Rostock
    • German Centre for Neurodegenerative Diseases (DZNE)
  • Tina Dunkelmann
    • Department of Neurology, Neurodegeneration Research Laboratory (NRL)Universities of Rostock
  • Jan Stenzel
    • Department of Neurology, Neurodegeneration Research Laboratory (NRL)Universities of Rostock
  • Bruno Miroux
    • Laboratoire de Biologie Physico-Chimique des Protéines Membranaires, UMR 7099Institut de Biologie Physico-Chimique
  • Saleh Ibrahim
    • Department of DermatologyUniversity of Lübeck
  • Oliver von Bohlen und Halbach
    • Institute of AnatomyUniversity of Greifswald
  • Hans-Jochen Heinze
    • Department of Neurology, Neurodegeneration Research Laboratory (NRL)Universities of Rostock
    • Leibniz Institute for Neurobiology
  • Lary C. Walker
    • Yerkes National Primate Research Center and Department of NeurologyEmory University
  • Jörg A. Gsponer
    • Center for High-Throughput BiologyUniversity of British Columbia
    • Department of Neurology, Neurodegeneration Research Laboratory (NRL)Universities of Rostock
    • German Centre for Neurodegenerative Diseases (DZNE)
    • Leibniz Institute for Neurobiology
    • Department of Neurology, Neurodegeneration Research Laboratory (NRL)Universities of Magdeburg
Original Paper

DOI: 10.1007/s00401-012-0980-x

Cite this article as:
Scheffler, K., Krohn, M., Dunkelmann, T. et al. Acta Neuropathol (2012) 124: 199. doi:10.1007/s00401-012-0980-x

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.

Keywords

AbetaMitochondrial congenic miceConplasticAlzheimer’s diseaseAmyloid-betaMicrogliaMitochondria

Supplementary material

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

Copyright information

© Springer-Verlag 2012