Impact of Treadmill Running and Sex on Hippocampal Neurogenesis in the Mouse Model of Amyotrophic Lateral Sclerosis

Hippocampal neurogenesis in the subgranular zone (SGZ) of dentate gyrus (DG) occurs throughout life and is regulated by pathological and physiological processes. The role of oxidative stress in hippocampal neurogenesis and its response to exercise or neurodegenerative diseases remains controversial. The present study was designed to investigate the impact of oxidative stress, treadmill exercise and sex on hippocampal neurogenesis in a murine model of heightened oxidative stress (G93A mice). G93A and wild type (WT) mice were randomized to a treadmill running (EX) or a sedentary (SED) group for 1 or 4 wk. Immunohistochemistry was used to detect bromodeoxyuridine (BrdU) labeled proliferating cells, surviving cells, and their phenotype, as well as for determination of oxidative stress (3-NT; 8-OHdG). BDNF and IGF1 mRNA expression was assessed by in situ hybridization. Results showed that: (1) G93A-SED mice had greater hippocampal neurogenesis, BDNF mRNA, and 3-NT, as compared to WT-SED mice. (2) Treadmill running promoted hippocampal neurogenesis and BDNF mRNA content and lowered DNA oxidative damage (8-OHdG) in WT mice. (3) Male G93A mice showed significantly higher cell proliferation but a lower level of survival vs. female G93A mice. We conclude that G93A mice show higher hippocampal neurogenesis, in association with higher BDNF expression, yet running did not further enhance these phenomena in G93A mice, probably due to a ‘ceiling effect’ of an already heightened basal levels of hippocampal neurogenesis and BDNF expression

Evidence For The Control Of Aggrecanases By Insulin And Glucose In Alzheimer'S Disease

Objective: Alzheimer's disease (AD) is a progressive and irreversible central nervous system disease, which slowly destroys cognitive skills and memory, and eventually even the ability to handle the simplest tasks. The initiation and progression of AD is a poorly understood complex process. Here, we have investigated possible biological mechanisms that could be responsible for the increased risk for diminished brain function associated with diabetes in AD. Method: The U87 cell line (human primary glioblastoma cell line) was cultured in Dulbecco's modified Eagle's medium. Cells were incubated with insulin (10 mu g/ml), low glucose (11 mM, 2 mg/ml) and high glucose (55 mM, 10 mg/ml) for 48 hours. Cells were harvested and protein isolations were performed. Primary anti-ADAMTS5, anti-IL-33, anti-NF kappa B, and anti-GAPDH antibodies were used to detect corresponding proteins and to measure band densities in Western membranes using a specific program. Results: Western blot analysis showed ADAMTS5 protein decreases in insulin-applied U87 cells. High glucose application led to a notable increase in ADAMTS5 levels in cells, while low glucose application caused a moderate increase in ADAMTS5 levels. An apparent induction of IL-33 protein was observed in high glucose-applied cells, while a moderate decrease was noted in the low-glucose applied group. Insulin administration led to a decrease in IL-33 levels. Immunoreaction of NF kappa B with corresponding antibody was found to be sharply decreased in insulin-applied cells while low and high glucose application led to a moderate decrease in NF kappa B. Conclusion: This is the first reported study that has investigated both aggrecanases and inflammation mediators in the same experimental setup with U87 cells and interpreted the results in the various aspects of AD pathophysiology related to diabetes and hyperglycemia. Our findings suggest that insulin and glucose may have important functions in the synthesis of ADAMTS, IL-33, and NF kappa B through undefined mechanism(s). Further investigations dealing with all aggrecanases and other class of ADAMTS enzymes should be carried out together with the above-mentioned parameters with the collaboration of molecular biology, genetics, immunology, and other related disciplines in order to elaborate the pathophysiological importance of ADAMTS enzymes and inflammation mediators in AD.WoSScopu