ABSTRACT
Alzheimer's disease (AD) is a multifactorial disease with genetic (70%) and environmental (30%) causes. Among the genetic factors are genes associated with a family history of the disease (familial AD, FAD) and sporadic AD (SAD). The genes: APP (amyloid precursor protein), PSEN1 (Presenilin 1) and PSEN2 (Presenilin 2) are responsible for the presence of FAD. The APOE gene is responsible for the sporadic form of the disease. Other molecular factors related to the immunological cause (TREM2) of the disease are a disorder of the lipid (ABCA1, ABCA7) or biothiol (MTHFD1) metabolism and of the transport of metabolites (BIN1). Currently, it is believed that APOE is a risk factor for both SAD and late-onset FAD. The pathomechanism of AD is most commonly explained as based on the amyloid cascade theory. This theory is related to the FAD, although there are reports indicating the probability of its occurrence in the SAD. It seems that the excessive deposition of ß-amyloid (Aß) peptides and intracellular neurofibrillary tangles of tau protein hyperphosphorylated forms contribute to the damage of both DNA and RNA. Furthermore, it is believed that RNA-interference can affect both the level of pathological proteins (Aß, tau protein) and the onset and progress of AD. It seems that a complete understanding of both FAD and SAD pathogenesis may contribute to the search for earlier clinical diagnosis and to an understanding of later occurrence of the disease, which may help modify its course and affect more effective therapy of this incurable neurological disease.
Subject(s)
Alzheimer Disease/genetics , Alzheimer Disease/metabolism , Alzheimer Disease/drug therapy , Animals , HumansABSTRACT
Alzheimer's disease (AD) leads to generation of ß-amyloid (Aß) in the brain. Alzheimer's disease model PS/APP mice show a markedly accelerated accumulation of Aß, which may lead to apoptosis induction e.g. in cells expressing wild-type p53. The TP53 gene is found to be the most frequently mutated gene in human tumour cells. There is accumulating evidence pointing out to the contribution of oxidative stress and chronic inflammation in both AD and cancer. The purpose of this study was to analyze exon 7 mutations of the murine Trp53 gene and Aß/A4 and p53 protein levels in PS/APP and control mice. The studies were performed on female double transgenic PS/APP mice and young adults (8-12 weeks old) and age-matched control mice. The Trp53 mutation analysis was carried out with the use of PCR and DNA sequencing. The Aß/A4 and p53 levels were analyzed by Western blotting. The frequency of mutations was almost quadrupled in PS/APP mice (44%), compared to controls (14%). PS/APP mice with the A929T and A857G mutations had a similar p53 level. In cerebral gray matter of PS/APP mice the level of p53 positive correlated with the level of Aß protein (RS = +0.700, p < 0.05). In younger control animals, the T854G mutation was related to p53 down-regulation, while in aging ones, G859A substitution was most likely associated with over-expression of p53. In silico protein analysis revealed a possibly substantial impact of all four mutations on p53 activity. Three mutations were in close proximity to zinc-coordinating cysteine residues. It seems that in PS/APP mice missense Trp53 exon 7 mutations may be associated with the degenerative process by changes of p53 protein function.
Subject(s)
Alzheimer Disease/genetics , Tumor Suppressor Protein p53/genetics , Alzheimer Disease/metabolism , Amyloid beta-Peptides , Animals , Blotting, Western , Brain/pathology , Disease Models, Animal , Exons/genetics , Female , Mice , Mice, Inbred C57BL , Mice, Transgenic , Mutation , Polymerase Chain Reaction , Tumor Suppressor Protein p53/biosynthesisABSTRACT
The aim of the study was to determine the extent of oxidative DNA damage (levels of 8-oxo2dG) and expression of OGG1 and p53 and TNF-α proteins in lymphocytes of Alzheimer's disease (AD) patients and a control group. The studies were conducted on 41 patients with AD, including 25 women and 16 men aged 34-84 years. The control group included 51 individuals, 20 women and 31 men aged 22-83 years. The level of 8-oxo2dG was determined using HPLC/EC/UV, and the level of OGG1 and p53 and TNF-α proteins was determined with the Western blot method. The results showed that both proteins participating in DNA repair (OGG1, p53) and the inflammatory protein TNF-α are involved in pathogenesis of neurodegenerative diseases. It also seems that a specific system for DNA repair (OGG1) may contribute to downregulation of the inflammatory factor (TNF-α) level, especially in the early stages of dementia. Moreover, the results showed that p53 protein can fulfil its function in DNA damage repair only in early stages of dementia. It is possible that OGG1 and p53 and TNF-α proteins together or separately may be involved in pathogenesis of AD by repair of oxidative DNA damage and/or apoptosis.
