Cellular signaling and Trafficking of APP Family Members

描述(由申请人提供)： 家族性阿尔茨海默病基因产物淀粉样β蛋白(ABeta)前体蛋白(APP)被加工成ABeta，它被认为是阿尔茨海默病的主要罪魁祸首之一。APP首先由α-或β-分泌酶分别产生C83或C99膜系链片段进行细胞外加工，然后由跨膜区的伽马-分泌酶进行加工。β-和伽马-分泌酶的处理会导致ABeta和AID(APP细胞内域)的产生，AID(APP细胞内域)是从APP的极端羧基末端衍生出来的。最初的研究表明，AID可以降低细胞的凋亡阈值，最近的研究表明，它可以调节基因表达和细胞内钙稳态。APP是包括APLP1和APLP2分子在内的一个基因家族的成员。利用基因敲除小鼠的研究表明，APP、APLP1和APLP2具有部分冗余的功能和独特的作用。由于APP通过释放生物活性的AID多肽来传递信号，APLP1和APLP2也可能通过g-分泌酶的处理而释放具有生物活性的APP样胞内域ALID。当前提案的主要目标是表征由APP、APLP1和APLP2处理调控的信号通路。这些研究可能会揭示每个APP家族成员共同的或特定的、独特的信号通路。在此背景下，我们还将研究APP家族成员在初级神经元中的贩运。APP在神经元中的转运可能与APP在神经细胞中的生物学功能密切相关，并可能调节神经突起的生长。这些研究可能阐明APP家族成员的生物学作用，并在开发治疗和或预防阿尔茨海默病的新化合物方面具有重要的实际应用。

DESCRIPTION (provided by applicant): The familial Alzheimer's disease gene product amyloid Beta (ABeta) precursor protein (APP) is processed to generate ABeta which is considered to be one of the major culprits of Alzheimer's disease. APP is first processed extracellularly by the alpha- or Beta-secretase creating either a C83 or C99 membrane tether fragment, respectively, and then by the gamma-secretase in the transmembrane domain. Processing by the Beta- and gamma-secretase leads to production of ABeta as well as AID (APP Intracellular Domain) which is derived from APP's extreme carboxy terminus. AID was originally shown to lower the cellular threshold to apoptosis and more recently has been shown to modulate gene expression and cellular calcium homeostasis. APP is a member of a gene family that includes the APP like molecules APLP1 and APLP2. Studies using knock out mice have demonstrated that APP, APLP1 and APLP2 have partially redundant functions as well as unique roles. Since APP signals by releasing the biologically active AID peptide, it is possible that APLP1 and APLP2 also release biologically active APP Like Intracellular Domains ALIDs due to processing by the g-secretase. The major goals of the current proposal are to characterize the signaling pathways regulated by APP, APLP1 and APLP2 processing. These studies could unveil the signaling pathways that are either common or specific and unique to each APP family member. In this context, we will also study the trafficking of APP family members in primary neurons. The transport of APP in neurons may be of great relevance to the biological function of APP in neuronal ceils and may regulate neurite growth. These studies may clarify the biological role of APP family members and have important practical applications in the development of new compounds for the cure and or prevention of Alzheimer's disease.