Search

Alzheimer's disease is a chronic neurodegenerative disorder marked by a progressive loss of memory and cognitive function. Stress level glucocorticoids are correlated with dementia progression in patients with Alzheimer's disease. In this study, twelve month old male mice were chronically treated for 21 days with stress-level dexamethasone (5mg/kg). We investigated the pathological consequences of dexamethasone administration on learning and memory impairments, amyloid precursor protein processing and neuronal cell apoptosis in 12-month old male mice. Our results indicate that dexamethasone can induce learning and memory impairments, neuronal cell apoptosis, and mRNA levels of the amyloid precursor protein, beta-secretase and caspase-3 are selectively increased after dexamethasone administration. Immunohistochemistry demonstrated that amyloid precursor protein, caspase-3 and cytochrome c in the cortex and CA1, CA3 regions of the hippocampus are significantly increased in 12-month old male mice. Furthermore, dexamethasone treatment induced cortex and hippocampus neuron apoptosis as well as increasing the activity of caspase-9 and caspase-3. These findings suggest that high levels of glucocorticoids, found in Alzheimer's disease, are not merely a consequence of the disease process but rather play a central role in the development and progression of Alzheimer's disease. Stress management or pharmacological reduction of glucocorticoids warrant additional consideration of the regimen used in Alzheimer's disease therapies.

In this study, the memory and learning impairment induced by dexamethasone in young mice and senescent mice were evaluated by step-down inhibitory avoidance task and passive avoidance test. Colorimetric MTT(tetrazole 3-(4,5-dimethylthiazol-2-yl-)-2,5-diphenyltetrazolium bromide) assay and TUNEL staining were used to investigate the influence of dexamethasone on hippocampal neuronal cell death with amyloid beta-protein. It was determined the effect of dexamethasone on intracellular calcium ([Ca(2+)](i)) with amyloid beta-protein 25-35 by fluorescence imaging with a confocal laser microscope using fluo-3 acetoxymethylester (AM) as a fluorescent dye. The effect of dexamethasone on amyloid beta-protein 25-35-induced nuclear factor kappaB (NF-kappaB) was analyzed by western blot. The results showed that twenty one days dexamethasone exposure resulted in an impairment of memory and learning in senescent but not young mice. Pretreatment of isolated hippocampal neurons with dexamethasone increased the vulnerability of the hippocampal neurons to amyloid beta-protein 25-35, enhanced [Ca(2+)](i) and down-regulated the increased level of nuclear NF-kappaB p65 proteins induced by amyloid beta-protein 25-35. These results demonstrated that glucocorticoids could potentiate the neurotoxic action of amyloid beta-protein by further increasing the level of [Ca(2+)](i) and down-regulating the level of nuclear NF-kappaB protein. Since amyloid beta-protein increases in the brain with aging, glucocorticoids potentiation of the neurotoxic action of amyloid beta-protein maybe one of the mechanisms responsible for glucocorticoids-induced memory and learning impairment in senescent but not young mice, which maybe relevance to the etiology of Alzheimer's disease.