title: Defective mitochondrial respiration, altered dNTP pools and reduced AP endonuclease 1 activity in peripheral blood mononuclear cells of Alzheimer's disease patients.
abstract: OBJECTIVE
  Accurate biomarkers for early diagnosis of Alzheimer's disease (AD) are badly needed. Recent reports suggest that dysfunctional mitochondria and DNA damage are associated with AD development. In this report, we measured various cellular parameters, related to mitochondrial bioenergetics and DNA damage, in peripheral blood mononuclear cells (PBMCs) of AD and control participants, for biomarker discovery.
  
  
  METHODS
  PBMCs were isolated from 53 patients with AD of mild to moderate degree and 30 age-matched healthy controls. Tests were performed on the PBMCs from as many of these participants as possible. We measured glycolysis and mitochondrial respiration fluxes using the Seahorse Bioscience flux analyzer, mitochondrial ROS production using flow cytometry, dNTP levels by way of a DNA polymerization assay, DNA strand breaks using the Fluorometric detection of Alkaline DNA Unwinding (FADU) assay, and APE1 incision activity (in cell lysates) on a DNA substrate containing an AP site (to estimate DNA repair efficiency).
  
  
  RESULTS
  In the PBMCs of AD patients, we found reduced basal mitochondrial oxygen consumption, reduced proton leak, higher dATP level, and lower AP endonuclease 1 activity, depending on adjustments for gender and/or age.
  
  
  CONCLUSIONS
  This study reveals impaired mitochondrial respiration, altered dNTP pools and reduced DNA repair activity in PBMCs of AD patients, thus suggesting that these biochemical activities may be useful as biomarkers for AD.
authors.affiliation: Department of Cellular and Molecular Medicine, Center for Healthy Aging, University of Copenhagen, 2200 Copenhagen, Denmark.
authors.forename: Scott
authors.initials: S
authors.lastname: Maynard
authors.affiliation: Department of Neurology, Danish Dementia Research Centre, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark.
authors.forename: Anne-Mette
authors.initials: AM
authors.lastname: Hejl
authors.affiliation: Department of Cellular and Molecular Medicine, Center for Healthy Aging, University of Copenhagen, 2200 Copenhagen, Denmark.
authors.forename: Thuan-Son T
authors.initials: TS
authors.lastname: Dinh
authors.affiliation: Department of Cellular and Molecular Medicine, Center for Healthy Aging, University of Copenhagen, 2200 Copenhagen, Denmark.
authors.forename: Guido
authors.initials: G
authors.lastname: Keijzers
authors.affiliation: Department of Public Health, University of Copenhagen, 1014 Copenhagen, Denmark.|The National Research Centre for the Working Environment, 2100 Copenhagen, Denmark.
authors.forename: Åse M
authors.initials: ÅM
authors.lastname: Hansen
authors.affiliation: Department of Cellular and Molecular Medicine, Center for Healthy Aging, University of Copenhagen, 2200 Copenhagen, Denmark.
authors.forename: Claus
authors.initials: C
authors.lastname: Desler
authors.affiliation: Molecular Toxicology Group, University of Konstanz, D-78457 Konstanz, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Moreno-Villanueva
authors.affiliation: Molecular Toxicology Group, University of Konstanz, D-78457 Konstanz, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Bürkle
authors.affiliation: Department of Cellular and Molecular Medicine, Center for Healthy Aging, University of Copenhagen, 2200 Copenhagen, Denmark.
authors.forename: Lene J
authors.initials: LJ
authors.lastname: Rasmussen
authors.affiliation: Department of Neurology, Danish Dementia Research Centre, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark.
authors.forename: Gunhild
authors.initials: G
authors.lastname: Waldemar
authors.affiliation: Department of Cellular and Molecular Medicine, Center for Healthy Aging, University of Copenhagen, 2200 Copenhagen, Denmark.|Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224-6825, USA.
authors.forename: Vilhelm A
authors.initials: VA
authors.lastname: Bohr
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000367:Age Factors; D000368:Aged; D000544:Alzheimer Disease / Q000378:metabolism*; D015415:Biomarkers / Q000378:metabolism; D016022:Case-Control Studies; D019069:Cell Respiration; D003071:Cognition; D053960:DNA Breaks; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000378:metabolism*; D004734:Energy Metabolism; D005260:Female; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism*; D009711:Nucleotides / Q000378:metabolism; D012737:Sex Factors
chemical_list: D015415:Biomarkers; D009711:Nucleotides; D000255:Adenosine Triphosphate; C085108:APEX1 protein, human; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase
keywords: APE1; Alzheimer's disease; DNA repair; bioenergetics; dNTP pools; mitochondria; peripheral blood mononuclear cells; reactive oxygen species