Neurosteroid DHEA is biosynthesized in neurons and glia, regulating neuronal survival and neurogenesis during development and aging. We provide evidence that DHEA acts as a neurotrophic factor, protecting neuronal cells against apoptosis via activation of TrkA and p75 NTR , membrane receptors of neurotrophin NGF. Specifically, we have shown that siRNA against prosurvival TrkA receptors blocked the anti-apoptotic effect of DHEA. Radiolabeled [ 3 H]DHEA bound with high affinity to membranes isolated from HEK293 cells transfected with the cDNAs of TrkA and p75 NTR receptors.DHEA-polyethylene-glycol beads effectively pulled down recombinant TrkA and p75 NTR proteins, and precipitated both proteins from extracts prepared from cells expressing both receptors. DHEA effectively activated NGF receptor-mediated signaling; Shc, Akt, and ERK1/2 kinases down-stream to TrkA receptors and TRAF6, RIP2 and RhoGDI effectors of p75 NTR receptor. Finally, DHEA rescued sensory neurons of dorsal root ganglia from apoptosis in NGF null embryos and compensated NGF in rescuing sympathetic neurons of embryonic superior cervical ganglia. Our findings suggest that DHEA and NGF crosstalk via their activation of NGF receptors to afford brain shaping and maintenance.Phylogenetic findings on the evolution of neurotrophins, their receptors and CYP17, the enzyme responsible for DHEA biosynthesis, combined with our data support the hypothesis that DHEA served as a phylogenetically ancient neurotrophic factor.