Estrogen, aging, and LTP in apoE replacement mice

使用雌激素改善老年女性的认知能力是有争议的，因为 它的好处是否超过其他健康风险的不确定性。ApoE epsilon 4(ApoE4)等位基因的存在日益被认为是年龄相关性认知功能下降的独立危险因素。一些证据表明雌激素-载脂蛋白E的相互作用可能是异构体特异性的。在这个试点项目的范围内，我们将检查apoE epsilon4等位基因的存在、雌激素治疗的年龄和雌激素治疗的节奏作为雌激素治疗疗效的三个潜在缓解因素。为了实现这些目标，我们将使用 长时程增强(LTP)的电生理范式，在齿状回测量，如In 记忆形成和神经修复的体外模型。我们将比较这两种亚急性疾病的影响 和慢性雌激素给药对LTP的影响 中年卵巢切除(OVX)人靶向替换apoE3和apoE4小鼠。 该项目将提供载脂蛋白E亚型和载脂蛋白E之间相互作用的新信息。 雌激素，并将补充正在进行的淀粉样β蛋白和载脂蛋白E亚型对突触可塑性的影响的研究。总之，这些研究将有助于确定体外突触可塑性受损的危险因素之间的等级，并将导致未来对潜在细胞机制的研究(即通过膜片钳实验)。它们还将作为未来行为研究的补充，阐明与年龄相关的记忆丧失的脆弱性，包括与阿尔茨海默病有关的记忆丧失，最终目标是挽救神经可塑性，减缓或防止认知能力下降。

The administration of estrogen to improve cognition in aging women is controversial because of uncertainty about whether its benefits outweigh other health risks. The presence of the APOE epsilon 4 (apoE4) allele is increasingly recognized as an independent risk factor for age-related cognitive decline. Several lines of evidence suggest an estrogen-apoE interaction that may be isoform specific. Within the scope of this pilot project we will examine the presence of the apoE epsilon4 allele, age at estrogen administration, and tempo of estrogen administration as three potential mitigating factors in the efficacy of estrogen therapy. To address these aims we will use the electrophysiologic paradigm of long-term potentiation (LTP), measured in dentate gyrus, as an in vitro model of memory formation and neural repair. We will compare the effects of both subacute and chronic estrogen delivery on LTP using hippocampal slices prepared from young adult and middle-aged ovariectomized (OVX) human targeted replacement apoE3 and apoE4 mice. This project will provide novel information about interactions among apoE isoform and estrogen, and will complement ongoing investigations of the effects of amyloid-beta and apoE isoform on synaptic plasticity. Together these studies will help define a hierarchy among risk factors for impaired synaptic plasticity in vitro and will lead to future studies of the underlying cellular mechanisms (i.e., via patch clamp experiments). They will also serve as a complement to future behavioral studies in the elucidation of vulnerability to age-related memory loss, including that related to Alzheimer disease, with the ultimate goal of neuroplasticity rescue and the slowing or prevention of cognitive decline.