POSTSYNAPTIC MECHANISMS OF SYNAPTIC-DEPENDENT A^ REGULATION IN VIVO

项目总结(见说明)： 降低淀粉样蛋白B的水平是最有可能治疗或预防这种疾病的方法。淀粉样蛋白B是一种积聚并导致阿尔茨海默氏症的多肽。我们的初步数据表明，突触后信号机制，主要是通过NMDA和增食欲素受体，可以显著减少AB的产生和水平。 我们认为，这两个神经递质系统激活了本质上不同的信号级联，最终汇聚在细胞外调节激酶(ERK)信号通路上。ERK信号通路的激活迅速并显著降低了体内的AB水平。这一提议将确定将这些神经递质受体与ERK和AB代谢联系起来的细胞通路。了解这些途径将有助于深入了解导致疾病风险的因素，并为治疗AD提供新的靶向途径。

PROJECT SUMMARY (See instructions): Reducing levels of amyloid-B, the peptide that accumulates and causes Alzheimer's disease, is the most likely method to treat or prevent this disease. Our preliminary data demonstrates that postsynaptic signaling mechanisms, mainly through NMDA and orexin receptors, can dramatically reduce AB production and levels. We propose that both of these neurotransmitter systems activate substantially different signaling cascades that eventually converge on the extracellular-regulated kinase (ERK) signaling pathway. Activation of the ERK signaling cascade rapidly and dramatically reduces AB levels in vivo. This proposal will determine the cellular pathways that link these neurotransmitter receptors to ERK and AB metabolism. Understanding these pathways will provide insight into factors that contribute to disease risk as well as provide new pathways that could be targeted for therapeutic inten/enfion to treat AD.