Studies of intracellular cascades mediating neuronal damage in two animal models of neurodegeneration

2013-10-07Alzheimer’s disease is characterized by progressive memory loss and cognitive deficits, accumulation of ß-amyloid plaques and intracellular neurofibrillary tangles within the brain, and neuronal death. In addition to ß-amyloid and tau pathology, mitochondrial dysfunction and free radical damage are also hallmarks of AD brain, suggesting that oxidative stress might be important in AD pathology. In the companion study we set out to define the role oxidative stress plays in AD pathogenesis by chronically treating mice that model human AD with the superoxide dismutase (SOD)/catalase mimetic, EUK-207, starting before the onset of pathology and cognitive deficits, and continuing until 9 months of age, when the AD phenotype is established. In the present study, we initiated the treatment after the onset of pathology at 9 months of age. After 3 months of treatment, cognitive performance, brain ß-amyloid and tau pathology as well as oxidative stress were analyzed. At 12 months of age, 3xTg-AD mice exhibited a decline in performance in both contextual and cued fear memory tasks as compared to wild-type mice; EUK-207-treated 3xTg-AD mice did not display any deficit in fear conditioning performance, as compared to wild-type controls. Chronic treatment with EUK-207 protected against increased levels of oxidized nucleic acids and lipid peroxidation in brain and reduced ß-amyloid, tau and hyperphosphorylated tau accumulation in amygdala and hippocampus of 3xTg-AD mice. Our results thus confirm a critical role for oxidative stress in AD progression and strongly suggest the potential usefulness for salen-manganese complexes as a treatment for AD. ❧ Systemic injection of kainate produces repetitive seizure activity in both adult and juvenile rats. However, while kainate-induced seizure results in neurodegeneration in the limbic system of adult rats, juvenile rats have been repeatedly shown to be immune to the neurotoxic effects of kainate. The mechanisms underlying this differential effect of seizure activity in adult and juvenile rat brain are not clear. We previously reported that kainate-induced seizure activity differentially affected calpain activation in neonatal and adult rat brain. We recently discovered that calpain could truncate the phosphatase PTEN, resulting in mTOR activation and stimulation of protein synthesis, including Arc synthesis. In the present study, we evaluated the effects of kainate-induced seizure activity on levels of calpain, PTEN, mTOR, and Arc in hippocampus from adult and postnatal rats. In adult rats, seizure activity rapidly stimulated calpain-2, as evidenced by decreased in drebrin and PTEN levels throughout the hippocampus. It was also associated with increased mTOR and Arc levels in fields CA1 and CA3 4 h after seizure initiation. PTEN truncation was blocked by systemic injection of the calpain inhibitor calpepetin before KA injection, but mTOR and Arc levels were not affected. Interestingly, in p12-14 rats, seizure activity was not associated with a rapid calpain activation and PTEN loss in any field of hippocampus, possibly due to lack of ERK activation. However, levels of mTOR were increased 1 day after seizure initiation, but levels of PTEN and Arc remained unchanged. These results indicate that seizure activity produces very different effects on the calpain→PTEN→mTOR and Arc cascade in hippocampus from juvenile and adult rats. Whether these different effects are related to the different neuropathological consequences of seizure activity remains to be determined