Alzheimer's disease (AD) 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 AD. In this study, 12-month male mice were chronically treated with stress-level dexamethasone (DEX, 5 mg/kg) and extract of Astragalus (EA, 10, 20, and 40 mg/kg) or Ginsenoside Rg1 (Rg1, 6.5 mg/kg) for 21 days. We investigated the protective effect of EA against DEX injury in mice and its action mechanism. Our results indicate that DEX can induce learning and memory impairments and neuronal cell apoptosis. The mRNA levels of caspase-3 are selectively increased after DEX administration. The results of immunohistochemistry demonstrate that caspase-3 and cytochrome c in hippocampus (CA1, CA3) and neocortex are significantly increased. Furthermore, DEX treatment increased the activity of caspase-9 and caspase-3. Treatment groups with EA (20 and 40 mg/kg) or Rg1 (6.5 mg/kg) significantly improve learning and memory, downregulate the mRNA level of caspase-3, decrease expression of caspase-3 and cytochrome c in hippocampus (CA1, CA3) and neocortex, and inhibit activity of caspase-9 and caspase-3. The present findings highlight a possible mechanism by which stress level of DEX accelerates learning and memory impairments and increases neuronal apoptosis and the potential neuronal protection of EA. Anat Rec,, 2011. © 2011 Wiley-Liss, Inc.