ABSTRACT
Recent studies have suggested that DNA methylation is implicated in age-related changes in gene expression as well as in cognition. DNA methyltransferase 3a (Dnmt3a), which catalyzes DNA methylation, is essential for memory formation and underlying changes in neuronal and synaptic plasticity. Because caloric restriction (CR) and upregulation of antioxidants have been suggested as strategies to attenuate age-related alterations in the brain, we hypothesized that both a diet restricted in calories and transgenic overexpression of normal human Cu/Zn superoxide dismutase 1 (SOD) attenuate age-related changes in Dnmt3a in the aging mouse hippocampus. For this purpose, we performed qualitative and quantitative analyses of Dnmt3a-immunoreactivity (IR) for the hippocampal dentate gyrus (DG), CA3 and CA1-2 regions in 12- and 24-month-old mice from 4 groups, i.e. (1) wild-type (WT) mice on a control diet (WT-CD), (2) SOD-CD mice, (3) WT mice on CR (WT-CR), and (4) SOD-CR. Qualitative analyses revealed two types of Dnmt3a immunoreactive cells: type I cells--present throughout all hippocampal cell layers showing moderate levels of nuclear Dnmt3a-IR, and type II cells--a subpopulation of hippocampal cells showing very intense nuclear Dnmt3a-IR, and colocalization with Bromodeoxyuridine. Quantitative analyses indicated that the age-related increase in Dnmt3a-IR within the CA3 and CA1-2 in type I cells was attenuated by CR, but not by SOD overexpression. In contrast, the density of type II Dnmt3a immunoreactive cells showed an age-related reduction, without significant effects of both CR and SOD. These changes in Dnmt3a levels in the mouse hippocampus may have a significant impact on gene expression and associated cognitive functioning.
Subject(s)
Aging/physiology , Caloric Restriction , DNA (Cytosine-5-)-Methyltransferases/metabolism , Hippocampus/enzymology , Superoxide Dismutase/metabolism , Animals , DNA Methyltransferase 3A , Energy Metabolism/physiology , Female , Gene Expression Regulation/physiology , Hippocampus/cytology , Humans , Immunohistochemistry , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Up-RegulationABSTRACT
The etiology of the sporadic form of Alzheimer's disease (AD) remains largely unknown. Recent evidence has suggested that gene-environment interactions (GxE) may play a crucial role in its development and progression. Whereas various susceptibility loci have been identified, like the apolipoprotein E4 allele, these cannot fully explain the increasing prevalence of AD observed with aging. In addition to such genetic risk factors, various environmental factors have been proposed to alter the risk of developing AD as well as to affect the rate of cognitive decline in AD patients. Nevertheless, aside from the independent effects of genetic and environmental risk factors, their synergistic participation in increasing the risk of developing AD has been sparsely investigated, even though evidence points towards such a direction. Advances in the genetic manipulation of mice, modeling various aspects of the AD pathology, have provided an excellent tool to dissect the effects of genes, environment, and their interactions. In this paper we present several environmental factors implicated in the etiology of AD that have been tested in transgenic animal models of the disease. The focus lies on the concept of GxE and its importance in a multifactorial disease like AD. Additionally, possible mediating mechanisms and future challenges are discussed.
ABSTRACT
Application of extracorporeal shockwaves (ESW) to the musculoskeletal system may induce long-term analgesia in the treatment of chronic tendinopathies of the shoulder, heel and elbow. However, the molecular and cellular mechanisms behind this phenomenon are largely unknown. Here we tested the hypothesis that long-term analgesia caused by ESW is due to selective loss of nerve fibers in peripheral nerves. To test this hypothesis in vivo, high-energy ESW were applied to the ventral side of the right distal femur of rabbits. After 6 weeks, the femoral and sciatic nerves were investigated at the light and electron microscopic level. Application of ESW resulted in a selective, substantial loss of unmyelinated nerve fibers within the femoral nerve of the treated hind limb, whereas the sciatic nerve of the treated hind limb remained unaffected. These data might indicate that alleviation of chronic pain by selective partial denervation may play an important role in the effects of clinical ESW application to the musculoskeletal system.