ABSTRACT
Age-related changes are increased in patients with Alzheimer's disease (AD), including oxidative stress and DNA damage. We propose that genotoxic stress and DNA repair responses influence neurodegeneration in the pathogenesis of AD. Here, we focus on nucleotide excision repair (NER). Real-time qPCR and mass spectrometry were employed to determine the expression levels of selected NER components. The mRNA levels of the genes encoding the NER proteins RAD23B, RPA1, ERCC1, PCNA and LIG3 as well as the NER-interacting base excision repair protein MPG in blood and brain tissue from four brain regions in patients with AD or mild cognitive impairment and healthy controls (HC), were assessed. NER mRNA levels were significantly higher in brain tissue than in blood. Further, LIG3 mRNA levels in the frontal cortex was higher in AD versus HC, while mRNA levels of MPG and LIG3 in entorhinal cortex and RPA1 in the cerebellum were lower in AD versus HC. In blood, RPA1 and ERCC1 mRNA levels were lower in AD patients than in HC. Alterations in gene expression of NER components between brain regions were associated with AD, connecting DNA repair to AD pathogenesis and suggesting a distinct role for NER in the brain.
Subject(s)
Alzheimer Disease/metabolism , Brain/metabolism , DNA Ligase ATP/metabolism , DNA Repair Enzymes/metabolism , DNA Repair/physiology , DNA-Binding Proteins/metabolism , Endonucleases/metabolism , Poly-ADP-Ribose Binding Proteins/metabolism , Proliferating Cell Nuclear Antigen/metabolism , Replication Protein A/metabolism , Alzheimer Disease/blood , DNA Ligase ATP/blood , DNA Repair Enzymes/blood , DNA-Binding Proteins/blood , Endonucleases/blood , Female , Humans , Male , Oxidative Stress/physiology , Poly-ADP-Ribose Binding Proteins/blood , Proliferating Cell Nuclear Antigen/blood , Replication Protein A/bloodABSTRACT
The current molecular understanding of Alzheimer's disease (AD) has still not resulted in successful interventions. Mitochondrial dysfunction of the AD brain is currently emerging as a hallmark of this disease. One mitochondrial function often affected in AD is oxidative phosphorylation responsible for ATP production, but also for production of reactive oxygen species (ROS) and for the de novo synthesis of pyrimidines. This paper reviews the role of mitochondrial produced ROS and pyrimidines in the aetiology of AD and their proposed role in oxidative degeneration of macromolecules, synthesis of essential phospholipids and maintenance of mitochondrial viability in the AD brain.
Subject(s)
Alzheimer Disease/metabolism , Alzheimer Disease/pathology , Mitochondria/metabolism , Mitochondria/pathology , Animals , Humans , Phospholipids/biosynthesis , Phospholipids/chemistry , Pyrimidines/biosynthesis , Pyrimidines/chemistry , Reactive Oxygen Species/metabolismABSTRACT
Mitochondrial dysfunction and DNA damage is intimately connected to ageing and neurodegeneration, including Alzheimer's disease (AD). A particular culprit in this context is oxidative stress, which is a result of increased reactive oxygen species (ROS) due to hyperactive or dysfunctional mitochondria and/or reduced DNA repair capacity. Base excision repair (BER) is the major pathway for repairing oxidative damage events in chromosomal and mitochondrial DNA. Defects in BER have been detected in ageing and neurodegeneration. Mitochondrial transcription factor A (TFAM) plays an important role in the maintenance of mitochondrial DNA integrity. The present study investigated single nucleotide polymorphisms (SNPs) in the genes encoding the BER components MutYH, OGG1, APE1, PolB and PolG and the gene encoding mitochondrial TFAM in a cohort of 161 AD patients, 96 non-AD patient controls (PC) and 192 healthy controls (HC). Notably, the minor allele carriers of APE1 rs1130409 and the common allele carriers of TFAM rs1937 were associated with reduced mini-mental state examination score in AD patients, PC and HC, with no distinction of SNP frequencies in either of these sub-groups. Collectively, the results suggest an association between DNA maintenance and decline in cognitive function. These studies enlighten the normal brain aging process and point to potential new biomarkers for cognitive function and impairment.
Subject(s)
Alzheimer Disease/genetics , Cognition Disorders/genetics , DNA-(Apurinic or Apyrimidinic Site) Lyase/genetics , DNA-Binding Proteins/genetics , Mitochondrial Proteins/genetics , Transcription Factors/genetics , Aged , Aged, 80 and over , Alleles , Alzheimer Disease/psychology , Amyloid beta-Peptides/cerebrospinal fluid , Biomarkers/cerebrospinal fluid , Case-Control Studies , Cognition Disorders/psychology , DNA Damage/genetics , DNA Polymerase gamma , DNA Repair/genetics , DNA-Directed DNA Polymerase/genetics , Genetic Association Studies , Genetic Predisposition to Disease , Heterozygote , Humans , Middle Aged , Polymorphism, Single Nucleotide , Reactive Oxygen Species/metabolism , tau Proteins/cerebrospinal fluidABSTRACT
BACKGROUND: Alzheimer's disease (AD) is a progressive, multifactorial neurodegenerative disorder that is the main cause of dementia globally. AD is associated with increased oxidative stress, resulting from imbalance in production and clearance of reactive oxygen species (ROS). ROS can damage DNA and other macromolecules, leading to genome instability and disrupted cellular functions. Base excision repair (BER) plays a major role in repairing oxidative DNA lesions. Here, we compared the expression of BER components APE1, OGG1, PARP1 and Polß in blood and postmortem brain tissue from patients with AD, mild cognitive impairment (MCI) and healthy controls (HC). RESULTS: BER mRNA levels were correlated to clinical signs and cerebrospinal fluid biomarkers for AD. Notably, the expression of BER genes was higher in brain tissue than in blood samples. Polß mRNA and protein levels were significantly higher in the cerebellum than in the other brain regions, more so in AD patients than in HC. Blood mRNA levels of OGG1 was low and PARP1 high in MCI and AD. CONCLUSIONS: These findings reflect the oxidative stress-generating energy-consumption in the brain and the importance of BER in repairing these damage events. The data suggest that alteration in BER gene expression is an event preceding AD. The results link DNA repair in brain and blood to the etiology of AD at the molecular level and can potentially serve in establishing novel biomarkers, particularly in the AD prodromal phase.
Subject(s)
Alzheimer Disease/blood , Alzheimer Disease/genetics , Brain/pathology , DNA Repair/genetics , Aged , Aged, 80 and over , Alzheimer Disease/cerebrospinal fluid , Alzheimer Disease/diagnosis , Biomarkers/cerebrospinal fluid , Case-Control Studies , DNA Glycosylases/genetics , DNA Glycosylases/metabolism , DNA Polymerase beta/genetics , DNA Polymerase beta/metabolism , DNA-(Apurinic or Apyrimidinic Site) Lyase/genetics , DNA-(Apurinic or Apyrimidinic Site) Lyase/metabolism , Female , Gene Expression Regulation , High-Throughput Nucleotide Sequencing , Humans , Male , Middle Aged , Poly (ADP-Ribose) Polymerase-1/genetics , Poly (ADP-Ribose) Polymerase-1/metabolism , Prodromal Symptoms , RNA, Messenger/blood , RNA, Messenger/genetics , Real-Time Polymerase Chain Reaction , Sequence Analysis, RNAABSTRACT
Alzheimer's disease (AD) is a disease of major public health significance, whose pathogenesis is strongly linked to the presence of fibrillar aggregates of amyloid-beta (Aß) in the aging human brain. We exploited the transgenic (Tg)-ArcSwe mouse model for human AD to explore whether oxidative stress and the capacity to repair oxidative DNA damage via base excision repair (BER) are related to Aß pathology in AD. Tg-ArcSwe mice express variants of Aß, accumulating senile plaques at 4-6 months of age, and develop AD-like neuropathology as adult animals. The relative mRNA levels of genes encoding BER enzymes, including 8-oxoguanine glycosylase (OGG1), AP endonuclease 1 (APE1), polymerase ß (Polß) and poly(ADP-ribose) polymerase 1 (PARP1), were quantified in various brain regions of 6 weeks, 4 months and 12 months old mice. The results show that OGG1 transcriptional expression was higher, and APE1 expression lower, in 4 months old Tg-ArcSwe than in wildtype (wt) mice. Furthermore, Polß transcriptional expression was significantly lower in transgenic 12 months old mice than in wt. Transcriptional profiling also showed that BER repair capacity vary during the lifespan in Tg-ArcSwe and wt mice. The BER expression pattern in Tg-ArcSwe mice thus reflects responses to oxidative stress in vulnerable brain structures.
Subject(s)
Alzheimer Disease/enzymology , Brain/enzymology , DNA Glycosylases/biosynthesis , DNA Polymerase beta/biosynthesis , DNA-(Apurinic or Apyrimidinic Site) Lyase/biosynthesis , Gene Expression Regulation, Enzymologic , Nerve Tissue Proteins/biosynthesis , Poly(ADP-ribose) Polymerases/biosynthesis , Alzheimer Disease/genetics , Alzheimer Disease/pathology , Animals , Brain/pathology , DNA Damage , DNA Glycosylases/genetics , DNA Polymerase beta/genetics , DNA Repair/genetics , DNA-(Apurinic or Apyrimidinic Site) Lyase/genetics , Disease Models, Animal , Humans , Mice , Mice, Transgenic , Nerve Tissue Proteins/genetics , Oxidative Stress/genetics , Poly (ADP-Ribose) Polymerase-1 , Poly(ADP-ribose) Polymerases/genetics , Transcription, Genetic/geneticsABSTRACT
To test the hypothesis that single nucleotide polymorphisms (SNPs) in DNA repair genes are associated with cognitive performance during normal aging, the relationship between SNPs in selected exons in DNA base excision repair (BER) genes and cognitive performance was examined in 712 healthy Norwegian individuals aged 20-75 years. SNPs examined included PolB(Pro242Arg), hOGG1(Ser326Cys), MutYH (Met22Val), MutYH(His324Gln), APE1(Gln51His), APE1(Glu148Asp), XRCC1(Lys298Asn), XRCC1(Arg7Leu), NEIL1(Asp252Asn), and NEIL2(Arg257Leu). XRCC1(Arg7Leu) and PolB(Pro242Arg) were characterized by single nucleotide variations (≤0.1% homozygote SNPs). hOGG1(Ser326Cys) (Ser/Cys 40.8%/Cys/Cys 5.7%), MutYH(His324Gln) (His/Gln37%/Gln/Gln 6.0%) and APE1(Glu148Asp) (Glu/Asp 51.3%/Asp/Asp 23.0%) were characterized by higher SNP frequencies. MutYH(Met22Val), APE1(Gln51His) and NEIL2(Arg257Leu) occurred at intermediate SNP frequencies of 11.5, 7.6 and 5.3%, respectively. Interestingly, hOGG1(Ser326Cys) and APE1(Gln51His) had genotype by age interactions with general cognitive function, reasoning, control and speed of processing in cross-sectional analysis and a significant effect on longitudinal decline. Dispersed association effects involving MutYH(His324Gln), MutYH(Met22Val), PolB(Pro242Arg) and NEIL2(Arg257Leu) were also detected when APOE or CHRNA4, were included in the statistical model, a result consistent with proposed involvement of the latter markers in human cognitive decline and/or function. In summary, the results support the notion that polymorphisms in BER genes modulate cognitive performance in healthy elderly individuals.
