title: Mitochondrial DNA polymorphisms specifically modify cerebral β-amyloid proteostasis.
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.
authors.affiliation: Department of Neurology, Neurodegeneration Research Laboratory (NRL), Universities of Rostock, Rostock, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Scheffler
authors.forename: Markus
authors.initials: M
authors.lastname: Krohn
authors.forename: Tina
authors.initials: T
authors.lastname: Dunkelmann
authors.forename: Jan
authors.initials: J
authors.lastname: Stenzel
authors.forename: Bruno
authors.initials: B
authors.lastname: Miroux
authors.forename: Saleh
authors.initials: S
authors.lastname: Ibrahim
authors.forename: Oliver
authors.initials: O
authors.lastname: von Bohlen Und Halbach
authors.forename: Hans-Jochen
authors.initials: HJ
authors.lastname: Heinze
authors.forename: Lary C
authors.initials: LC
authors.lastname: Walker
authors.forename: Jörg A
authors.initials: JA
authors.lastname: Gsponer
authors.forename: Jens
authors.initials: J
authors.lastname: Pahnke
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism*; D004272:DNA, Mitochondrial / Q000235:genetics* / Q000378:metabolism; D005260:Female; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000235:genetics; D011110:Polymorphism, Genetic
chemical_list: D016229:Amyloid beta-Peptides; D004272:DNA, Mitochondrial