AGED FOREBRAIN CHOLINERGIC NEURONS--ESTROGEN AND NGF

描述：(改编自《调查者摘要》) 老龄化和与年龄相关的退行性疾病受到越来越多的关注 它在西方世界的社会经济影响。即使有 在阿尔茨海默病等与年龄相关的疾病中，我们仍然存在显著的性别差异 不知道是哪些内部或外部因素控制着这一过程。广告是 以前脑胆碱能神经元的显著丧失为标志，这种疾病 女性比男性更常见。淀粉样前体的错误处理 蛋白(APP)可能在AD中起重要作用，AD的高发 对于老年女性来说，更年期和大脑中缺乏雌激素是可能的。 来自组织培养实验的最新证据表明，多因素 以及APP、类固醇激素与NGF之间的关系。然而，没有 已经设计了活体模型来探索这种关系。Ts65Dn小鼠 Chr 16节段性三体(包括APP基因)有一个 APP过度表达、胆碱能前脑神经元丢失与认知 发生在6个月大左右的损伤。一个较短的Chr 16三体，Ts1Cje (不包括APP基因)缺乏认知障碍和胆碱能损失。这个 Ts65Dn小鼠可作为加速衰老的动物模型 神经退行性变，以检验APP、雌激素和NGF相互作用的假设 来维持胆碱能系统。使用以问题为基础的方法进行研究 在过去的五年里，该实验室使用了一种衰老的老鼠模型来 研究一种新的、非侵入性的NGF给药系统。这个交付系统现在将 用于研究Ts65Dn小鼠的记忆丧失和胆碱能变性。这个 具体目标是：1)应用程序处理和/或 大鼠前脑或海马区神经生长因子水平的变化 Ts65Dn小鼠胆碱能细胞丢失？2)去卵巢和雌激素 替代疗法改变认知功能障碍、胆碱能变性和/或 NGF/APP水平？3)野生型胆碱能神经元移植会屈服于 当移植到Ts65Dn宿主上时，同样的表型丢失？4)能不能治疗 使用NGF和/或雌激素可缓解认知改变和胆碱能 Ts65Dn小鼠的表型丢失？

DESCRIPTION: (Adapted from the Investigator's Abstract) Aging and age-related degenerative disease has received increased attention due to its socioeconomic impact in the western world. Even though there are significant gender differences in age-related diseases such as AD, we still do not know which internal or external factors regulate this process. AD is signified by a marked loss of forebrain cholinergic neurons, and this disease occurs more often in women than men. Incorrect processing of amyloid precursor protein (APP) may play a significant role in AD, and the high incidence of AD in elderly women could depend on menopause and a lack of estrogen in the brain. Recent evidence from tissue culture experiments suggests a multifactorial process, and a relationship between APP, steroid hormones and NGF. However, no in vivo models have been designed to explore this relationship. Ts65Dn mice with segmental trisomy of Chr 16 (including the APP gene) have an overexpression of APP, loss of cholinergic forebrain neurons, and cognitive impairment that occurs around 6 months of age. A shorter Chr 16 trisomy, Ts1Cje (excluding the APP gene) lacks cognitive impairment and cholinergic loss. The Ts65Dn mouse can thus be used as a model for accelerated aging and neurodegeneration, to test the hypothesis that APP, estrogen and NGF interact to maintain the cholinergic system. Using a problem-based approach to study degeneration, the lab has used an aged rat model over the past five years to study a new, noninvasive delivery system for NGF. This delivery system will now be used to study memory loss and cholinergic degeneration in Ts65Dn mice. The specific aims are: 1) is there an alteration in APP processing and/or alterations in NGF levels in forebrain or hippocampus during the time of cholinergic cell loss in Ts65Dn mice? 2) Do ovariectomy and estrogen replacement therapy alter cognitive impairment, cholinergic degeneration and/or NGF/APP levels? 3) Do transplants of wildtype cholinergic neurons succumb to the same phenotype loss when grafted into a TS65DN host? And 4) Can treatment with NGF and/or estrogen alleviate cognitive alterations and cholinergic phenotype loss in the Ts65Dn mouse?