AGED FOREBRAIN CHOLINERGIC NEURONS--ESTROGEN AND NGF

老年前脑胆碱能神经元——雌激素和 NGF

• 批准号: 6131783
• 负责人: Ann-Charlotte Esther Granholm-Bentley
• 金额: $ 26.71万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-04-08 至 2005-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6131783
• 关键词: Alzheimer's disease; acetylcholine; aging; amyloid proteins; brain disorder chemotherapy; enzyme linked immunosorbent assay; estrogens; hormone therapy; laboratory mouse; nerve growth factors; nervous system transplantation; neural degeneration; neuroprotectants; nonhuman therapy evaluation; ovariectomy; prosencephalon; trisomy; western blottings

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?

描述：（根据调查员的摘要进行了改编） 衰老和与年龄有关的退行性疾病已受到越来越多的关注 它对西方世界的社会经济影响。即使有 与AD等年龄相关疾病的性别差异很大，我们仍然这样做 不知道哪些内部或外部因素调节此过程。广告是 以明显的前脑胆碱能神经元的明显丧失表示，这种疾病 女性比男性更频繁地发生。淀粉样前体的不正确处理 蛋白质（APP）可能在AD中起重要作用，并且AD的高发病率很高 在老年人中，妇女可能取决于更年期和大脑缺乏雌激素。 组织培养实验的最新证据表明多因素 过程，类固醇激素和NGF之间的关系。但是，不 体内模型旨在探索这种关系。 TS65DN小鼠 Chr 16（包括App基因）的分段三体性具有 APP的过表达，胆碱能的前脑神经元和认知 大约6个月大的损害。较短的CHR 16三体，TS1CJE （不包括应用程序基因）缺乏认知障碍和胆碱能丧失。这 因此，TS65DN小鼠可以用作加速衰老和 神经变性，以测试应用程序，雌激素和NGF相互作用的假设 维持胆碱能系统。使用基于问题的方法学习 变性，该实验室在过去五年中使用了老化的大鼠模型 研究NGF的新的无创递送系统。现在这个交付系统将 用于研究TS65DN小鼠的记忆丧失和胆碱能变性。这 具体目的是：1）应用程序处理和/或 NGF水平在前脑或海马中的改变 TS65DN小鼠中的胆碱能细胞损失？ 2）进行卵巢切除术和雌激素 替代疗法改变认知障碍，胆碱能变性和/或 NGF/APP级别？ 3）进行野生型胆碱能神经元的移植 将移植到TS65DN宿主中时相同的表型损失？ 4）可以治疗 NGF和/或雌激素可以减轻认知改变和胆碱能 TS65DN小鼠中的表型损失？