Targeting angiotensin II in cognitive impairment associated with ovarian hormone loss

在自然绝经前接受双侧卵巢切除术的妇女患卵巢癌的风险增加。 罹患包括阿尔茨海默病(AD)在内的痴呆症的女性比年龄匹配的女性更多。还有更多的需求 保护认知功能的治疗选择。自然发病前双侧卵巢切除术 更年期导致雌激素的产生突然停止，从而导致循环中的 雌激素(主要是17-雌二醇)。然而，关于雌激素替代的危害和好处的争议 认知治疗(ERT)仍在继续。即使ERT被证明能提供认知益处，ERT也是 一些妇女和其他人可能因为其他原因而不选择ERT。靶向肾素 血管紧张素系统提供了一种很有前途的新的治疗方法。患有高血压的个人在 增加与年龄相关的认知衰退和痴呆(包括阿尔茨海默病)的风险。不同类型的临床研究 抗高血压药物的种类表明，保护认知功能的效果各不相同。 与它们对血压(BP)的影响无关。多项临床研究显示血管紧张素1型 受体(AT1R)阻滞剂(ARB)在降低高血压风险方面优于其他抗高血压药物 包括阿尔茨海默病在内的认知功能减退或痴呆。这些临床研究结果表明，ARB对认知障碍有保护作用。 以依赖于BP和非依赖于BP的方式下降和转换为AD。对雄性动物的研究 支持ARB对认知的保护作用独立于其对 BP和研究表明，AT1R在AD中更活跃；然而，关于认知功能，人们知之甚少 ARB对自然绝经年龄前卵巢激素缺乏妇女的保护作用 到目前为止，还没有关于ARB对认知机制的影响的基础科学研究发表 在绝经前卵巢激素缺乏的女性模型中。在目标1中，我们将确定年龄的作用 雌激素丢失对脑阻力小动脉内皮细胞功能和海马神经病理的影响 在高血压和认知衰退模型中与阿尔茨海默病相关。在目标2中，我们将确定 神经元AT1R活性和血压对脑阻力血管、海马区内皮功能的影响 卵巢切除后RAS活性与神经病理和认知损害的关系。这项研究可能 为接受绝经前双侧手术的妇女设计新的治疗方法和干预试验 卵巢切除术以及为经历过的女性提供认知功能保护的见解 卵巢早衰和绝经后妇女。 1

Women who have undergone bilateral oophorectomy prior to natural menopause are at increased risk of developing dementia including Alzheimer's disease (AD) than age-matched women. There is a need for more therapeutic options to protect cognitive function. Bilateral oophorectomy before the onset of natural menopause causes an abrupt cessation of estrogen production with a consequent drop in circulating levels of estrogen (primarily 17-estradiol). Controversy, however, over the harm vs. benefit of estrogen replacement therapy (ERT) for cognition continues. Even if ERT is proven to provide cognitive benefits, ERT is contraindicated in some women and others may not elect ERT for other reasons. Targeting the renin angiotensin system offers a promising new therapeutic approach. Individuals with hypertension are at increased risk of age-associated cognitive decline and dementia including AD. Clinical studies with different classes of anti-hypertensive drugs have shown that effectiveness for protecting cognitive function varies independently of their effect on blood pressure (BP). Several clinical studies showed angiotensin type 1 receptor (AT1R) blockers (ARBs) to be superior to other antihypertensive drugs at reducing the risk of cognitive decline or dementia including AD. These clinical findings suggest that ARBs protect against cognitive decline and conversion to AD in both a BP-dependent and -independent manner. Studies in male animals support the clinical findings of ARBs exerting protective effects on cognition independently of their effects on BP and studies suggest AT1Rs are more active in AD; however, little is known regarding the cognitive protective effects of ARBs in women who are ovarian hormone deficient prior to the natural age of menopause and no basic science research has been published to date on the effects of ARBs on mechanisms of cognition in a female model of premenopausal ovarian hormone deficiency. In Aim 1, we will determine the role of age and estrogen loss on endothelial function in cerebral resistance arterioles and hippocampus neuropathology associated with AD in a model of hypertension and cognitive decline. In Aim 2, we will determine the role of neuronal AT1R activity and blood pressure on endothelial function in cerebral resistance vessels, hippocampus RAS activity and neuropathology and cognitive impairment as a function of ovariectomy. This research may inform the design of new therapeutics and intervention trials for women who undergo premenopausal bilateral oophorectomy as well as provide insights into protection of cognitive function for women who experience premature ovarian failure and post-menopausal women. 1