Long Term Running Biphasically Improves Methylglyoxal-Related Metabolism, Redox Homeostasis and Neurotrophic Support within Adult Mouse Brain Cortex

Oxidative stress and neurotrophic support decline seem to be crucially involved in brain aging. Emerging evidences indicate the pro-oxidant methylglyoxal (MG) as a key player in the age-related dicarbonyl stress and molecular damage within the central nervous system. Although exercise promotes the overproduction of reactive oxygen species, habitual exercise may retard cellular aging and reduce the age-dependent cognitive decline through hormetic adaptations, yet molecular mechanisms underlying beneficial effects of exercise are still largely unclear. In particular, whereas adaptive responses induced by exercise initiated in youth have been broadly investigated, the effects of chronic and moderate exercise begun in adult age on biochemical hallmarks of very early senescence in mammal brains have not been extensively studied. This research investigated whether a long-term, forced and moderate running initiated in adult age may affect the interplay between the redox-related profile and the oxidative-/MG-dependent molecular damage patterns in CD1 female mice cortices; as well, we investigated possible exercise-induced effects on the activity of the brain derived neurotrophic factor (BDNF)-dependent pathway. Our findings suggested that after a transient imbalance in almost all parameters investigated, the lately-initiated exercise regimen strongly reduced molecular damage profiles in brains of adult mice, by enhancing activities of the main ROS- and MG-targeting scavenging systems, as well as by preserving the BDNF-dependent signaling through the transition from adult to middle age

Nitric Oxide Decreases the Enzymatic Activity of Insulin Degrading Enzyme in APP/PS1 Mice

peer reviewedNitric oxide has been implicated in the regulation of enzyme activity, particularly the activity of metalloproteinases. Since the inducible form of the nitric oxide synthase (NOS2), is upregulated in Alzheimer's disease, we investigated the activity of two amyloid β degrading enzymes, IDE and neprilysin. In vitro we demonstrated that the activity of IDE was inhibited by *NO donor Sin-1, whereas activity of neprilysin remained unaffected. In vivo the activity of insulin-degrading enzyme was lowered in APP/PS1 mice, but not in APP/PS1/NOS2(-/-) mice. These data suggest that NOS2 upregulation impairs amyloid β degradation through negative regulation of IDE activity and thus loss of NOS2 activity will positively influence amyloid β clearance

Cell cycle related signalling in neuro2A cells proceeds via the receptor for advanced glycation end products

Re-expression of cell cycle related genes such as cyclin-dependent kinases (cdk), cyclins, or cdk inhibitors in differentiated neurons in Alzheimer’s disease (AD) is rooted in aberrant mitogenic signaling. Since microglia and astroglia proliferate in the vicinity of amyloid plaques, it is likely that plaque components or factors secreted from plaque-activated glia induce mitogenic signaling in neurons. Mitogenic compounds might be S100B, overexpressed by activated astrocytes, or advanced glycation end products (AGEs), a component of plaques. Both S100B and AGEs may interact with the multiligand receptor for AGEs (RAGE) and trigger for the activation of the p42/44 mitogen-activated protein kinase (p42/44 MAPK), whether they also count for cell cycle related signaling in neurons remains unresolved. By immunohistochemical staining, we confirmed that cyclin D1 positive neurons are surrounded by AGE deposits, demonstrating the potential relevance in vivo. For exploring the mitogenic signal cascade, we used Neuro2a cells overexpressing human full-length RAGE (FL-RAGE) or the cytosolic deletion mutant (Δ-RAGE). In both cell lines, S100B and AGEs induced the production of reactive oxygen species but not in a RAGE-dependent manner. By contrast, in FL-RAGE cells but not in Δ-RAGE cells S100B and AGEs activate p42/44 MAPK, augment cyclin D1/cdk4 protein and RNA levels and the transition into the S-phase. Moreover, in FL-RAGE cells, decreased protein levels of the cdk inhibitor p16 were observed, and the p42/44 MAPK inhibitor UO126 prevented AGE and S100B stimulated cyclin D1 expression and hindered cells to enter the S-phase. Our results demonstrate that S100B and AGE may serve as mitogenic sources for the stimulation of neurons to progress through the cell cycle whereby signaling proceeds via RAGE → p42/44 MAPK → cyclin D1/cdk4