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 β. 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.

DNA base excision repair activities in mouse models of Alzheimer's disease

“…However, APE1 activity in brains of AD patients was found similar to non-AD controls (Weissman et al, 2007). Accordingly, we report here that AP-site incision activity did not alter significantly in brain regions of symptomatic relative to pre-symptomatic 3xTgAD animals, nor did it change with age in WT mice.…”

“…HIP or FC), and incision activity of 5-OH-C remained unaffected. Similarly, uracil incision activity, which was found reduced in brain of human AD and MCI patients (Weissman et al, 2007), was only slightly altered in AD mice brain regions not typically associated with the disease.…”

“…This is followed by incorporation of one or several nucleotides into the gap by DNA polymerase and strand ligation by a DNA ligase. We have recently found significant functional deficiencies in BER in brains of sporadic AD and amnestic mild cognitive impairment (MCI) patients due to limited DNA base damage processing by DNA glycosylases and reduced DNA synthesis capacity by polymerase β (polβ) (Weissman et al, 2007). However, the question of how BER deficiency is involved in the progression of AD has yet to be answered.…”

“…Table 1). For polβ gap-filling reactions, we used an unlabeled double-stranded substrate containing a single-nucleotide gap (Weissman et al, 2007).…”

“…8-oxoG, an abundant mutagenic oxidized purine, and 5-OH-C, an oxidized pyrimidine, were previously shown to accumulate to a greater extent in affected human AD brain regions relative to aged matched controls (Gabbita et al, 1998;Wang et al, 2005). Oxoguanine DNA glycosylase (OGG1), the primary enzyme for the repair of 8-oxoG (Klungland et al, 1999;de Souza-Pinto et al, 2001), was found to be decreased in expression and activity in human AD brain tissues (Lovell et al, 2000;Iida et al, 2002;Weissman et al, 2007). Our present results show that in AD mice, 8-oxoG incision activity was not significantly altered in diseaseassociated brain regions (e.g.…”