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 β-amyloid 25–35 (Aβ25–35) 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 Aβ25–35-infusion. The DHEA-neuroprotection was blocked by the σ1 receptor antagonist NE100 and mimicked by the σ1 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 Aβ25–35-infusion decreased the levels of Akt, mTOR and p70S6k phosphorylation, which could be rescued by DHEA-treatment in a σ1 receptor-dependent manner. Furthermore, the Aβ25–35-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 Aβ25–35-impaired survival and dendritic growth of newborn neurons through a σ1 receptor-mediated modulation of PI3K-Akt-mTOR-p70S6k signaling.