Ovarian Hormones and Age-related Memory Deterioration

描述(由申请人提供)拟议研究的长期目标 是描述影响记忆和神经退化的因素 年迈的女性。老年和阿尔茨海默病-S病(AD)患者表现出记忆 下降，这与前脑胆碱能神经元和 投射区域，如海马体和皮质。广告在女性中更为普遍， 雌性大鼠表现出更早、更极端的与年龄相关的记忆衰退 而不是男性。这种夸大的记忆丧失可能与卵巢激素有关 拒绝。事实上，卵巢切除(OVX)损害了胆碱能神经元的完整性和 神经生长因子(NGF)水平。其他研究表明一种关系 在雌激素和β-淀粉样蛋白之间，这是AD斑块的主要成分。 这些效应可能为显示OVX的数据提供了生物学解释 会导致记忆力下降。这样的互动假说还没有被直接 测试过。我们建议在老年雌性大鼠身上测试OVX是否会加剧 大脑皮层、前脑和海马胆碱能的增龄性变化 神经元、NGF和淀粉样前体蛋白(APP)。此外，尽管雌激素 替代疗法可改善记忆力，降低心脏病、中风和AD的风险 在更年期女性中，这是有争议的，因为它也会增加癌症风险。 雷洛昔芬是一种SERM，在乳房和子宫中充当雌激素拮抗剂， 而是一种脂肪和骨骼的激动剂。由于雷洛昔芬增加了轴突的生长 一种细胞系和去卵巢大鼠海马区ChAT活性，它还可能 提高记忆力。我们建议测试雷洛昔芬是否像雌激素一样影响 工作记忆和参考记忆、前脑胆碱能细胞完整性、神经生长因子和 APP在老年雌性大鼠中的应用。由于目前尚无治疗阿尔茨海默病的方法，我们希望 这种跨学科的研究将有助于发现新的和 更有效的治疗方法。

DESCRIPTION (provided by applicant) The long-term goal of the proposed research is to characterize factors that influence memory and neural deterioration in aging females. Aged and Alzheimer?s disease (AD) patients exhibit memory decline, which is related to deterioration of forebrain cholinergic neurons and projection areas such as hippocampus and cortex. AD is more prevalent in women, and female rats show an earlier and more-extreme age-related memory decline than males. This exaggerated memory loss may be related to ovarian hormone decline. Indeed, ovariectomy (Ovx) compromises cholinergic neuron integrity and nerve growth factor (NGF) levels. Other research suggests a relationship between estrogen and beta-amyloid, the main constituent of plaques seen in AD. These effects may provide a biological explanation for data showing that Ovx results in memory decline. Such an interactive hypothesis has not been directly tested. We propose to test, in aging female rats, whether Ovx exacerbates age-related changes in cortical, forebrain, and hippocampal cholinergic neurons, NGF, and amyloid precursor protein (APP). Further, although estrogen replacement improves memory and decreases risk of heart disease, stroke, and AD in menopausal women, it is controversial since it also increases cancer risk. Raloxifene is a SERM that acts as an estrogen antagonist in breast and uterus, but an agonist in lipid and bone. Since raloxifene increased neurite growth in a cell line and ChAT activity in the hippocampus in Ovx rats, it may also improve memory. We propose to test whether raloxifene, like estrogen, affects working and reference memory, forebrain cholinergic cell integrity, NGF, and APP in aging female rats. Since there is no known cure for AD, we hope that this type of interdisciplinary research will aid in the discovery of new and more efficacious therapies.