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， 老年女性老年人和阿尔茨海默病？阿尔茨海默病（AD）患者表现出记忆力 下降，这与前脑胆碱能神经元的退化有关， 投射区域，如海马和皮质。AD在女性中更为普遍， 而雌性大鼠表现出更早和更极端的与年龄相关的记忆衰退 比男性多。这种夸张的记忆丧失可能与卵巢激素有关 下降事实上，卵巢切除术（Ovx）损害胆碱能神经元的完整性， 神经生长因子（NGF）水平。其他研究表明， 雌激素和β-淀粉样蛋白之间的关系，β-淀粉样蛋白是AD斑块的主要成分。 这些效应可能为数据显示Ovx 导致记忆力下降这种互动的假设并没有被直接 测试.我们建议在衰老的雌性大鼠中测试卵巢切除是否会加剧 皮质、前脑和海马胆碱能神经元的年龄相关变化 神经元、NGF和淀粉样前体蛋白（APP）。此外，虽然雌激素 替代可改善记忆力，降低心脏病、中风和AD的风险 在绝经期妇女中，它是有争议的，因为它也增加了癌症的风险。 雷洛昔芬是一种SERM，在乳腺和子宫中作为雌激素拮抗剂， 而是脂质和骨骼的激动剂由于雷洛昔芬增加神经突起生长， a细胞系和卵巢切除大鼠海马中ChAT活性，也可能 提高记忆力。我们建议测试雷洛昔芬是否像雌激素一样， 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， 老年雌性大鼠的APP。由于没有已知的治疗AD的方法，我们希望， 这种跨学科的研究将有助于发现新的， 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.