Department of Pathology and Pathophysiology, School of Basic Medicine, Key Laboratory of Neurological Disease of National Education Ministry, Institute for Brain Research, Huazhong University of Science and Technology, Wuhan, China.
Affiliated Wuhan Mental Health Center, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
J Alzheimers Dis. 2020;77(3):1077-1093. doi: 10.3233/JAD-200486.
Women are reported more likely to develop depression and dementia. However, the involved mechanism is poorly understood.
Here, we clarified the role of estrogen receptor α (ERα) in depression and cognitive deficit in young female rats.
After being exposed to 7-weeks' chronic unpredicted mild stress (CUMS), the depression resilient rats (Res rats) and depressed rats (Dep rats) were selected according to their records in sucrose preference test, forced swimming test, and open field test. Their cognition abilities were tested by Morris water maze. Proteomic assay, immunoprecipitation, western blotting, immunohistochemical, and Nissl staining were also used to understand the involved mechanism.
Compared with control rats and Res rats, Dep rats showed cognitive deficits and hippocampal impairments revealed by proteomic data, neuron losses, increased cleaved caspase-3, β-catenin phosphorylation, and glycogen synthase kinase3β (GSK3β) activation. As ERα, but not ERβ, was found declined in hippocampi of Dep rats, 4,4k,4a-(4-propyl-[1H]-pyrazole-1,3,5-triyl) trisphenol (PPT, an ERα agonist, 1 mg/kg/day), was used to treat Dep rats (Dep + PPT). Twenty days later, the depressive behaviors, cognition deficits, and hippocampal neuron loss were rescued in Dep + PPT rats. Furthermore, Res and Dep + PPT rats had higher levels of β-catenin combined with ERα and lower levels of β-catenin combined with GSK3β than Dep rats in hippocampi.
These results demonstrated hippocampal ERα is an important pro-resilient factor in CUMS-induced depressive behaviors and cognitive deficits. It was also given that the neuroprotection afforded by hippocampal ERα/Wnt interactions have significant implications for cognition and emotion in young females.
据报道，女性更易患抑郁症和痴呆症。然而，其涉及的机制尚不清楚。
本研究旨在阐明雌激素受体 α（ERα）在年轻雌性大鼠抑郁和认知缺陷中的作用。
经过 7 周的慢性不可预测轻度应激（CUMS）暴露后，根据蔗糖偏好试验、强迫游泳试验和旷场试验的记录，选择抗抑郁大鼠（Res 大鼠）和抑郁大鼠（Dep 大鼠）。采用 Morris 水迷宫测试评估它们的认知能力。还使用蛋白质组学分析、免疫沉淀、Western blot、免疫组织化学和尼氏染色来了解相关机制。
与对照大鼠和 Res 大鼠相比，Dep 大鼠表现出认知缺陷和海马损伤，这些损伤通过蛋白质组学数据、神经元丢失、增加的 cleaved caspase-3、β-连环蛋白磷酸化和糖原合酶激酶 3β（GSK3β）激活得到证实。由于 ERα而非 ERβ在 Dep 大鼠的海马中减少，因此使用 4,4k,4a-(4-丙基-[1H]-吡唑-1,3,5-三基)三苯酚（PPT，一种 ERα激动剂，1 mg/kg/天）治疗 Dep 大鼠（Dep+PPT）。20 天后，Dep+PPT 大鼠的抑郁行为、认知缺陷和海马神经元丢失得到挽救。此外，Res 和 Dep+PPT 大鼠的海马中 ERα 结合的β-连环蛋白水平高于 Dep 大鼠，而 ERα 结合的 GSK3β 水平低于 Dep 大鼠。
这些结果表明，海马 ERα 是 CUMS 诱导的抑郁行为和认知缺陷的重要抗抑郁因素。此外，海马 ERα/Wnt 相互作用提供的神经保护对年轻女性的认知和情绪具有重要意义。
