Regional hippocampal differences in AKT survival signaling across the lifespan: Implications for CA1 vulnerability with aging

Distinct neuronal populations differ by the degree of damage caused from cellular stress. Hippocampal neurons of area CA1 are especially vulnerable to several stressors that increase with advanced age. We show here that survival signaling, as measured by activated AKT, was significantly reduced in the nuclear CA1 region across the lifespan compared to CA3. In agreement with these findings the pro-apoptotic protein, and AKT nuclear substrate, FOXO3a was significantly higher in CA1. Further, regional differences in PHLPP1, a recently discovered inhibitor of AKT, inversely correlated with nuclear phosphorylated AKT at Ser473. Together our data suggest that regional differences in nuclear levels of activated AKT may contribute to regional differences in hippocampal vulnerability, and implicate PHLPP1 as a potential target for therapeutic intervention to improve hippocampal health.