Progesterone, aging, and memory loss

这一提议的广泛假设是，与年龄相关的激素变化会影响与年龄相关的认知变化。最终的目标是通过激素调节来减缓大脑老化和认知能力的衰退。有证据表明，绝经期的激素损失加剧了认知能力的下降，并导致女性阿尔茨海默病（AD）患病率的增加，而激素治疗可以减弱这些影响。然而，最近的研究发现， 雌激素/孕激素治疗增加女性痴呆风险。其他研究发现，联合治疗对认知能力有害，而仅使用雌激素则不然。我们假设，雌激素单独有益于认知，孕激素改变雌激素的作用，导致联合激素治疗的负面结果。我们最近发现卵巢切除术（Ovx）对年轻大鼠的认知能力有害，但对老年大鼠的认知能力有增强作用。由于孕酮在老年大鼠中升高，我们假设， 升高的孕酮有助于提高分数。我们接下来的研究表明，黄体酮治疗确实逆转了Ovx对老年大鼠的认知增强作用。这些发现，与数据表明，孕激素增强年轻Ovx大鼠的认知能力，使我们假设，Ovx和孕激素对年轻与老年人的大脑有不同的影响。虽然研究已经测试了雌激素单独对大脑和认知的影响，但很少有研究测试孕酮单独或与 雌二醇这是目前赠款提案的目标。具体目标我测试的假设，孕酮是有害的记忆和相关的神经参数，这种影响取决于年龄。实验1将评估Ovx和Ovx加孕酮治疗在从成年到老年的年龄范围内的效果。这将更好地定义Ovx从对空间记忆有害转变为有益的年龄。具体目标2检验孕激素抵消雌激素对记忆和神经参数的影响的假设 与年龄相关的认知变化有关。实验2将比较雌激素和雌激素/孕激素治疗在雌激素增强认知的年龄的影响。在这两项研究中，迷宫电池将评估空间和非空间的工作和参考记忆，产生一个全面的认知概况。随后将评估淀粉样前体蛋白（APP）加工和神经营养因子水平，这两者都会因年龄和激素而改变。这些研究是阐明卵巢激素在衰老过程中对认知的影响的下一步，并将指导未来的研究。他们可能会深入了解为什么一些临床试验 表明雌激素单独有益于认知和AD风险，而雌激素/孕激素没有。拟议的研究还将详细说明记忆和神经功能，这些功能会随着年龄的增长，卵巢激素的流失以及雌激素单独或雌激素/孕激素组合的治疗而受到损害。

The broad hypothesis of this proposal is that age-related hormone change affects age-related cognitive change. The ultimate goat is to attenuate brain aging and cognitive deterioration via hormonal modulation. There is evidence that hormone loss at menopause exacerbates cognitive decline and contributes to the increased prevalence of Alzheimer's disease (AD) in women, and that hormone therapy attenuates these effects. However, recent studies found that combined estrogen/progesterone therapy increased dementia risk in women. Other research found that combined treatment was detrimental to cognitive performance, while estrogen-only was not. We hypothesize that estrogen alone benefits cognition, and that progesterone alters estrogen's effects resulting in a negative outcome of combined hormone treatment. We recently found that ovariectomy (Ovx) was detrimental to cognition in young rats, but enhanced cognition in aged rats. Since progesterone was elevated in aged rats, we hypothesized that removal of elevated progesterone contributed to enhanced scores. Our next study showed that, indeed, progesterone treatment reversed the cognitive enhancing effect of Ovx in aged rats. These findings, taken with data indicating that progesterone enhanced cognitive profiles in young Ovx rats, leads us to hypothesize that Ovx and progesterone have different effects on the young vs aged brain. Although studies have tested the effects that estrogen alone has on the brain and cognition, few studies have tested the effects of progesterone alone or in conjunction with estradiol. This is the goal of the current grant proposal. Specific Aim I tests the hypothesis that progesterone is detrimental to memory and associated neural parameters, and that such effects depend on age. Experiment 1 will evaluate the effects of Ovx and Ovx plus progesterone treatment at ages ranging from adult to aged. This will better define the age at which Ovx transitions from detrimental to beneficial for spatial memory. Specific Aim 2 tests the hypothesis that progesterone counteracts the effects of estrogen on memory and neural parameters related to age-associated cognitive change. Experiment 2 will compare the effects of estrogen to estrogen/progesterone therapy at an age where estrogen enhances cognition. In both studies, a maze battery will evaluate spatial and non-spatial working and reference memory, yielding a thorough cognitive profile. This will be followed by assessment of amyloid precursor protein (APP) processing and neurotrophin levels, both of which are altered by age and hormones. These studies are the next step in elucidating ovarian hormone influences on cognition during aging and will direct future studies. They may yield insight into why several clinical trials indicate that estrogen alone benefits cognition and AD risk, while estrogen/progesterone does not. The proposed research will also detail the mnemonic and neural functions that are compromised with age, ovarian hormone loss, and therapies of estrogen alone or estrogen/progesterone combinations.