title: Mitochondrial DNA damage in a mouse model of Alzheimer's disease decreases amyloid beta plaque formation.
abstract: Mitochondrial DNA (mtDNA) damage and the generation of reactive oxygen species have been associated with and implicated in the development and progression of Alzheimer's disease. To study how mtDNA damage affects reactive oxygen species and amyloid beta (Aβ) pathology in vivo, we generated an Alzheimer's disease mouse model expressing an inducible mitochondrial-targeted endonuclease (Mito-PstI) in the central nervous system. Mito-PstI cleaves mtDNA causing mostly an mtDNA depletion, which leads to a partial oxidative phosphorylation defect when expressed during a short period in adulthood. We found that a mild mitochondrial dysfunction in adult neurons did not exacerbate Aβ accumulation and decreased plaque pathology. Mito-PstI expression altered the cleavage pathway of amyloid precursor protein without increasing oxidative stress in the brain. These data suggest that mtDNA damage is not a primary cause of Aβ accumulation.
authors.affiliation: Department of Neurology, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: Milena
authors.initials: M
authors.lastname: Pinto
authors.affiliation: Neuroscience Graduate Program, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: Alicia M
authors.initials: AM
authors.lastname: Pickrell
authors.affiliation: Neuroscience Graduate Program, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Fukui
authors.affiliation: Department of Neurology, University of Miami Miller School of Medicine, Miami, FL, USA.|Neuroscience Graduate Program, University of Miami Miller School of Medicine, Miami, FL, USA.|Department of Cell Biology and Anatomy, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: Carlos T
authors.initials: CT
authors.lastname: Moraes
mesh_terms: D000544:Alzheimer Disease / Q000209:etiology* / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000201:enzymology / Q000378:metabolism*; D004249:DNA Damage / Q000502:physiology*; D004272:DNA, Mitochondrial; D004195:Disease Models, Animal; D004720:Endonucleases / Q000378:metabolism / Q000502:physiology; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D058225:Plaque, Amyloid / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D004272:DNA, Mitochondrial; D017382:Reactive Oxygen Species; D004720:Endonucleases
keywords: APP cleavage; Alzheimer; Plaque formation; ROS; mtDNA damage