ESTROGEN, GLUTAMATE RECEPTOR IN PLASTICITY AND ALZHEIMER'S DISEASE

该项目涉及双重免疫的细胞机制， 雌激素在阿尔茨海默病妇女中的作用，即，的 改善认知缺陷，降低 雌激素替代治疗的女性AD。 的这些作用 雌激素提示雌激素或某些马雌激素成分 作为认知增强剂和/奥拉斯神经保护剂。 这些假设将在体外突触模型中进行检验。 可塑性和神经变性。 长时程增强（LTP） 被广泛认为代表了一种细胞信息机制 储存和调节LTP的化合物已经被发现 调节学习和记忆过程。 LTP诱导和 表达严重依赖于2类变力性 受体，NMDA和AMPA受体。 因此，具体目标1和2将旨在确定 急性和慢性雌激素治疗对海马神经元的影响 切片在培养中保持数周; 的AMPA和NMDA受体和LTP的性质。 用兴奋毒素或β-半乳糖苷处理培养的海马脑片， 淀粉样肽（β AP）产生选择性神经元损伤 其表现出AD中发生的神经元死亡的几个特征。 因此，具体目标3和4将评估神经保护性 雌激素在这些模型中的作用 雌激素在这些疾病中的作用 体外系统将与其在培养物中的作用进行比较， 分离的神经元以及突触的体内模型 可塑性和神经变性。

This project addresses the cellular mechanisms underlying the dual actions of estrogen in women with Alzheimer's Disease, i.e., the improvement of the cognitive deficits and the reduced incidence of AD in women with estrogen replacement therapy. These effects of estrogen suggest that estrogen or some equine estrogen constituent acts as a cognitive enhancer and/oras a neuroprotective agent. These hypothesis will be tested in in vitro models of synaptic plasticity and neurodegeneration. Long-term potentiation (LTP) is widely considered to represent a cellular mechanism for information storage and compounds modulating LTP have been found to modulate learning and memory processes. LTP induction and expression are critically dependent on 2 classes of inotropic receptors, the NMDA and the AMPA receptors, respectively. Specific Aims 1 and 2 will therefore be directed at determining the effects of acute and chronic estrogen treatment of hippocampal slices maintained in culture for several; weeks on the characteristics of AMPA and NMDA receptors and on the properties of LTP. Treatment of cultured hippocampal slices with excitotoxin or beta- amyloid peptide (betaAP) produces selective neuronal damage which exhibits several features of neuronal death occurring in AD. Specific Aims 3 and 4 will therefore evaluate the neuroprotective effects of estrogen in these models. Effects of estrogen in these in vitro systems will be compared with its effects in cultures of dissociated neurons as well as in in vivo models of synaptic plasticity and neurodegeneration.