DHEA prevents Aβ25-35-impaired survival of newborn neurons in the dentate gyrus through a modulation of PI3K-Akt-mTOR signaling

Infusion (i.c.v.) of beta-amyloid 25-35 (A beta(25-35)) stimulates proliferation of progenitor cells in the hippocampal dentate gyrus (DG) of adult male mice, but a large population of the newborn cells will die in the 2nd week after birth, a critical period for neurite growth. Neurosteroid dehydroepiandrosterone (DHEA) has been demonstrated to promote neurite growth. Herein, we report that the DHEA-treatment on 6-12 days after BrdU-injection (BrdU-D6-12) dose-dependently attenuates the loss of newborn neurons induced by A beta(25-35)-infusion. The DHEA-neuroprotection was blocked by the alpha(1) receptor antagonist NE100 and mimicked by the alpha(1) receptor agonist PRE084 when administered on BrdU-D6-12. The DHEA-action was sensitive to the PI3K inhibitor LY294002 and the mammalian target of rapamycin (mTOR) inhibitor rapamycin. The A beta(25-35)-infusion decreased the levels of Akt, mTOR and p7056k phosphorylation, which could be rescued by DHEA-treatment in a alpha(1) receptor-dependent manner. Furthermore, the A beta(25-35)-infusion led to a decrease in the dendritic density and length of doublecortin positive cells in the DG, which also was improved by the DHEA-treatment on BrdU-D6-12. These findings suggest that DHEA prevents the A beta(25-35)-impaired survival and dendritic growth of newborn neurons through a alpha(1) receptor-mediated modulation of PI3K-Akt-mTOR-p7056k signaling. (C) 2010 Elsevier Ltd. All rights reserved.