Mitochondrial DNA polymorphisms specifically modify cerebral β-amyloid proteostasis

• Type of Material: Article
• Authors: Katja Scheffler, Universities of Rostock and Magdeburg; Markus Krohn, Universities of Rostock and Magdeburg; Tina Dunkelmann, Universities of Rostock and Magdeburg; Jan Stenzel, Universities of Rostock and Magdeburg; Bruno Miroux, Institut de Biologie Physico-Chimique; Saleh Ibrahim, University of Lübeck; Oliver von Bohlen und Halbach, University of Greifswald; Hans-Jochen Heinze, Universities of Rostock and Magdeburg; Lary C Walker, Emory University; Jorg A. Gsponer, University of British Columbia; Jens Pahnke, Universities of Rostock and Magdeburg
• Language: English
• Date: 2012-08
• Publisher: Springer Verlag (Germany)
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © Springer-Verlag 2012
• Final Published Version (URL): http://dx.doi.org/10.1007/s00401-012-0980-x
• Title of Journal or Parent Work: Acta Neuropathologica
• ISSN: 0001-6322
• Volume: 124
• Issue: 2
• Start Page: 199
• End Page: 208
• Grant/Funding Information: 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.).
• Keywords: Abeta; mitochondria; Alzheimer’s disease; conplastic; microglia; amyloid-beta; congenic mice
• Research Categories: Biology, Neuroscience

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.