Is DNA repair compromised in Alzheimer's disease?
Mammalian cells utilize multiple mechanisms to repair DNA damage that occurs during normal cellular respiration and in response to genotoxic stress. This study sought to determine if chronic oxidative stress proposed to occur during Alzheimer's disease alters the expression or activity of DNA double-strand break repair or base excision repair proteins. Double-strand break repair requires DNA-dependent protein kinase, composed of a catalytic subunit, DNA-PKcs, and a regulatory component, Ku. Ku DNA binding activity was reduced in extracts of postmortem AD midfrontal cortex, but was not significantly different from the age-matched controls. Decreased Ku DNA binding correlated with reduced protein levels of Ku subunits, DNA-PKcs, and poly(ADP-ribose) polymerase-1. Expression of the base excision repair enzyme Ref-1, however, was significantly increased in AD extracts compared to controls. Ku DNA binding and DNA-PK protein levels in the AD cases correlated significantly with synaptophysin immunoreactivity, which is a measure of synaptic loss, a major correlate of cognitive deficits in AD. Immunohistochemical analysis suggested that DNA-PK protein levels reflected both number of neurons and regulation of cellular expression.
Davydov
Vladislav
V
Department of Neurosciences, University of California at San Diego, La Jolla, CA 92093-0624, USA.
Hansen
Lawrence A
LA
Shackelford
Deborah A
DA
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000201:enzymology* / Q000235:genetics*; D034961:Antigens, Nuclear / Q000378:metabolism*; D016022:Case-Control Studies; D004265:DNA Helicases; D004260:DNA Repair / Q000502:physiology*; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000378:metabolism; D051747:DNA-Activated Protein Kinase; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005260:Female; D005625:Frontal Lobe / Q000201:enzymology*; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D000072200:Ku Autoantigen; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins; D018384:Oxidative Stress / Q000502:physiology; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*
D034961:Antigens, Nuclear; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D011065:Poly(ADP-ribose) Polymerases; D051747:DNA-Activated Protein Kinase; C497263:PRKDC protein, human; D017346:Protein Serine-Threonine Kinases; D004265:DNA Helicases; C106893:XRCC5 protein, human; C000606509:Xrcc6 protein, human; D000072200:Ku Autoantigen; C085108:APEX1 protein, human; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase