title: Defective DNA base excision repair in brain from individuals with Alzheimer's disease and amnestic mild cognitive impairment.
abstract: Oxidative stress is thought to play a role in the pathogenesis of Alzheimer's disease (AD) and increased oxidative DNA damage has been observed in brain tissue from AD patients. Base excision repair (BER) is the primary DNA repair pathway for small base modifications such as alkylation, deamination and oxidation. In this study, we have investigated alterations in the BER capacity in brains of AD patients. We employed a set of functional assays to measure BER activities in brain tissue from short post-mortem interval autopsies of 10 sporadic AD patients and 10 age-matched controls. BER activities were also measured in brain samples from 9 amnestic mild cognitive impairment (MCI) subjects. We found significant BER deficiencies in brains of AD patients due to limited DNA base damage processing by DNA glycosylases and reduced DNA synthesis capacity by DNA polymerase beta. The BER impairment was not restricted to damaged brain regions and was also detected in the brains of amnestic MCI patients, where it correlated with the abundance of neurofibrillary tangles. These findings suggest that BER dysfunction is a general feature of AD brains which could occur at the earliest stages of the disease. The results support the hypothesis that defective BER may play an important role in the progression of AD.
authors: Laboratories of Molecular Gerontology, National Institute on Aging, NIH, Baltimore, MD 21224, USA.
authors: Lior
authors: L
authors: Weissman
authors: Dong-Gyu
authors: DG
authors: Jo
authors: Martin M
authors: MM
authors: Sørensen
authors: Nadja C
authors: NC
authors: de Souza-Pinto
authors: William R
authors: WR
authors: Markesbery
authors: Mark P
authors: MP
authors: Mattson
authors: Vilhelm A
authors: VA
authors: Bohr
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000201:enzymology* / Q000235:genetics; D000647:Amnesia / Q000201:enzymology* / Q000235:genetics; D001921:Brain / Q000201:enzymology*; D002531:Cerebellum / Q000201:enzymology; D045647:DNA Glycosylases / Q000378:metabolism; D019951:DNA Polymerase beta / Q000378:metabolism; D004260:DNA Repair; D045643:DNA Repair Enzymes / Q000378:metabolism*; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D010296:Parietal Lobe / Q000201:enzymology; D013577:Syndrome
chemical_list: D019951:DNA Polymerase beta; D045647:DNA Glycosylases; C085108:APEX1 protein, human; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; D045643:DNA Repair Enzymes
references: Brain Res. 2000 Feb 7;855(1):116-23
references: 10650137
references: Neurology. 1998 Oct;51(4):1014-7
references: 9781522
references: Mutat Res. 2000 Aug 30;460(3-4):231-44
references: 10946231
references: J Biol Chem. 2000 Sep 15;275(37):28607-17
references: 10884383
references: Neurobiol Aging. 2002 Jan-Feb;23(1):47-53
references: 11755018
references: Acta Neuropathol. 2002 Jan;103(1):20-5
references: 11837743
references: J Neurosci. 2002 Mar 1;22(5):1752-62
references: 11880504
references: J Biol Chem. 2002 Oct 25;277(43):40302-8
references: 12192006
references: Neurobiol Aging. 2003 Nov;24(7):953-68
references: 12928056
references: Nature. 2004 Jun 24;429(6994):883-91
references: 15190254
references: Biomarkers. 2004 Mar-Apr;9(2):203-9
references: 15370876
references: Trends Neurosci. 2004 Oct;27(10):601-6
references: 15374671
references: J Biol Chem. 2004 Oct 15;279(42):43952-60
references: 15297456
references: Biochemistry. 1974 Jul 30;13(16):3405-10
references: 4601435
references: J Mol Biol. 1977 Dec 5;117(2):293-306
references: 342701
references: Neurology. 1984 Jul;34(7):939-44
references: 6610841
references: Mutat Res. 1990 Mar;237(2):65-73
references: 1694967
references: Int J Neurosci. 1990 Feb;50(3-4):169-74
references: 2265895
references: Neuroreport. 1998 Aug 24;9(12):2749-52
references: 9760114
references: Trends Neurosci. 1998 Oct;21(10):428-33
references: 9786340
references: J Neurochem. 1998 Nov;71(5):2034-40
references: 9798928
references: Nucleic Acids Res. 1999 Apr 15;27(8):1935-42
references: 10101204
references: J Biol Chem. 1999 May 14;274(20):13741-3
references: 10318775
references: Biochemistry. 1999 Jun 15;38(24):7609-16
references: 10386999
references: Neurobiol Aging. 2005 May;26(5):567-73
references: 15708428
references: Am J Clin Nutr. 2005 Sep;82(3):636-43
references: 16155278
references: Ann Neurol. 2005 Oct;58(4):495-505
references: 16178023
references: J Neurochem. 2006 Feb;96(3):825-32
references: 16405502
references: Lancet. 2006 Apr 15;367(9518):1262-70
references: 16631882
references: Cancer Res. 2006 Aug 1;66(15):7460-5
references: 16885342
references: Clin Ther. 2006 Jul;28(7):991-1001
references: 16990077
references: J Neurosci. 2006 Oct 25;26(43):10949-57
references: 17065437
references: Mutat Res. 2007 Jan 3;614(1-2):24-36
references: 16879837
references: Acta Neuropathol. 1991;82(4):239-59
references: 1759558
references: Neurosci Lett. 1993 Nov 12;162(1-2):179-82
references: 8121624
references: Neurobiol Aging. 1997 Jul-Aug;18(4 Suppl):S1-2
references: 9330978
references: EMBO J. 1997 Oct 15;16(20):6314-22
references: 9321410
references: Nucleic Acids Res. 1998 Apr 15;26(8):2001-7
references: 9518496
references: EMBO J. 2000 Mar 15;19(6):1397-404
references: 10716939