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 (Abeta(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-D(6-12)) dose-dependently attenuates the loss of newborn neurons induced by Abeta(25-35)-infusion. The DHEA-neuroprotection was blocked by the sigma(1) receptor antagonist NE100 and mimicked by the sigma(1) receptor agonist PRE084 when administered on BrdU-D(6-12). The DHEA-action was sensitive to the PI3K inhibitor LY294002 and the mammalian target of rapamycin (mTOR) inhibitor rapamycin. The Abeta(25-35)-infusion decreased the levels of Akt, mTOR and p70S6k phosphorylation, which could be rescued by DHEA-treatment in a sigma(1) receptor-dependent manner. Furthermore, the Abeta(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-D(6-12). These findings suggest that DHEA prevents the Abeta(25-35)-impaired survival and dendritic growth of newborn neurons through a sigma(1) receptor-mediated modulation of PI3K-Akt-mTOR-p70S6k signaling. Copyright 2010 Elsevier Ltd. All rights reserved.