AGED FOREBRAIN CHOLINERGIC NEURONS--ESTROGEN AND NGF

描述：（改编自研究者摘要） 衰老和与年龄相关的退行性疾病受到越来越多的关注， 对西方社会经济的影响。即使有 在与年龄相关的疾病，如AD，我们仍然做显着的性别差异， 我们不知道是什么内部或外部因素影响了这一过程。AD是 前脑胆碱能神经元的明显缺失， 女性比男性更常见。淀粉样蛋白前体处理不正确 APP蛋白可能在AD发病中起重要作用， 老年妇女的抑郁症可能取决于更年期和大脑中缺乏雌激素。 组织培养实验的最新证据表明， 过程，以及APP，类固醇激素和NGF之间的关系。但没有 已经设计了体内模型来探索这种关系。ts 65 dn小鼠 与Chr 16（包括APP基因）的节段性三体有一个 APP的过度表达，胆碱能前脑神经元的丢失， 6个月左右出现的损伤。一种较短的Chr 16三体，Ts 1Cje （不包括APP基因）缺乏认知障碍和胆碱能损失。的 Ts 65 Dn小鼠因此可用作加速老化的模型， 神经变性，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基于问题的方法来研究 退化，该实验室在过去五年中使用了一种老年大鼠模型， 研究一种新的非侵入性的神经生长因子输送系统。这个输送系统现在 用于研究Ts 65 Dn小鼠的记忆丧失和胆碱能变性。的 具体目标是：1）APP处理和/或 在脑缺血期间前脑或海马中NGF水平的变化 Ts 65 Dn小鼠的胆碱能细胞丢失？2)做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水平？3)野生型胆碱能神经元的移植是否屈服于 当移植到TS 65 DN宿主中时相同的表型丢失？（4）可以治疗 与NGF和/或雌激素一起缓解认知改变和胆碱能 Ts 65 Dn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?