Metabolic alteration of neuroactive steroids and protective effect of progesterone in Alzheimer's disease-like rats

A correlation between metabolic alterations of neuroactive steroids and Alzheimer's disease remains unknown. In the present study, amyloid beta (A beta) 25-35 (A beta(25-35)) injected into the bilateral hippocampus CA1 region significantly reduced learning and memory. At the biochemical level, hippocampal levels of pregnenolone were significantly reduced with A beta(25-35) treatment. Furthermore, progesterone was considerably decreased in the prefrontal cortex and hippocampus, and 17 beta-estradiol was significantly elevated. To our knowledge, this is the first report showing that A beta(25-35), a main etiological factor of Alzheimer's disease, can alter the level and metabolism of neuroactive steroids in the prefrontal cortex and hippocampus, which are brain regions significantly involved in learning and memory. A beta(25-35) exposure also increased the expression of inflammatory mediators, tumor necrosis factor-alpha and interleukin-1 beta. However, subcutaneous injection of progesterone reversed the upregulation of tumor necrosis factor-alpha and interleukin-1 beta in a dose-dependent manner. Concomitant with improved cognitive abilities, progesterone blocked A beta-mediated inflammation and increased the survival rate of hippocampal pyramidal cells. We thus hypothesize that A beta-mediated cognitive deficits may occur via changes in neuroactive steroids. Moreover, our findings provide a possible therapeutic strategy for Alzheimer's disease via neuroactive steroids, particularly progesterone.