Transcriptomic Profile Identifies Hippocampal Sgk1 as the Key Mediator of Ovarian Estrogenic Regulation on Spatial Learning and Memory and Aß Accumulation.

Previous studies have shown that ovarian estrogens are involved in the occurrence and pathology of Alzheimer's disease (AD) through regulation on hippocampal synaptic plasticity and spatial memory; however, the underlying mechanisms have not yet been elucidated at the genomic scale. In this study, we established the postmenopausal estrogen-deficient model by ovariectomy (OVX). Then, we used high-throughput Affymetrix Clariom transcriptomics and found 143 differentially expressed genes in the hippocampus of OVX mice with the absolute fold change ≥ 1.5 and P < 0.05. GO analysis showed that the highest enrichment was seen in long-term memory. Combined with the response to steroid hormone enrichment and GeneMANIA network prediction, the serum and glucocorticoid-regulated kinase 1 gene (Sgk1) was found to be the most potent candidate for ovarian estrogenic regulation. Sgk1 overexpression viral vectors (oSgk1) were then constructed and injected into the hippocampus of OVX mice. Morris water maze test revealed that the impaired spatial learning and memory induced by OVX was rescued by Sgk1 overexpression. Additionally, the altered expression of synaptic proteins and actin remodeling proteins and changes in CA1 spine density and synapse density induced by OVX were also significantly reversed by oSgk1. Moreover, the OVX-induced increase in Aß-producing BACE1 and Aß and the decrease in insulin degrading enzyme were significantly reversed by oSgk1. The above results show that multiple pathways and genes are involved in ovarian estrogenic regulation of the function of the hippocampus, among which Sgk1 may be a novel potent target against estrogen-sensitive hippocampal dysfunctions, such as Aß-initiated AD.

Hippocampus-specific Rictor knockdown inhibited 17ß-estradiol induced neuronal plasticity and spatial memory improvement in ovariectomized mice.

Estrogens have been shown to play profound roles in the regulation of the structure and function of the hippocampus; however, the underlying mechanism is not clear. Previous studies have shown that when Rictor, the core component of the mammalian target of the rapamycin complex 2 (mTORC2), was deleted, hippocampal actin polymerization was reduced and long-term memory was seriously impaired. Although hippocampal Rictor could be regulated by estrogen receptor agonists/antagonists, whether Rictor could directly mediate estrogenic regulation of neuronal plasticity, spatial learning and memory remains unclear. In this study, we first examined the regulation of hippocampal Rictor and P-AKTser473 (P-AKT) by E2, then we used Rictor-specific dsRNA (shRictor) injected into the hippocampi of E2-treated ovariectomized (OVX) mice or into cultured cells. The results showed that both Rictor and P-AKT could be regulated by E2. OVX induced actin depolymerization, decreases in CA1 spine density and synapse density as well as changes in synaptic proteins were reversed by E2 replacement. However, these E2-mediated effects were significantly blocked by shRictor treatment. Similar results were also demonstrated by in vitro cell culture studies using E2 and/or shRictor. Importantly, we found that E2 replacement induced improvements in learning and memory impairment seen in OVX mice were significantly blocked by shRictor. Taken together, the current studies provided the first direct evidence for the important role of Rictor in estrogenic action on the hippocampus, indicating that it may be a therapeutic target for the treatment of E2-related, hippocampus-dependent cognitive dysfunction.