N-terminus of sAPP Regulates Abeta Assembly

淀粉样蛋白(Ass)的异常堆积、聚集和沉积是一种突出的 阿尔茨海默病(AD)及相关疾病的病理特征。屁股多肽是 由Ass前体蛋白(AssPP)经ss-和？- 偷偷摸摸活动。AsPP在脑中高度表达，但其生理功能仍然存在 人们对此知之甚少。已在ASPP蛋白的分泌型上确定了许多功能结构域 参与多种神经保护活动，从抑制蛋白水解酶到配体 结合到细胞保护上。例如，在前一个资助期内，我们明确表示 证明sASPP的KPI活性限制了脑损伤的程度。 血栓形成。额外的保护活性可能与其他生物活性结构域有关。 SASPP蛋白在包括慢性神经退行性变在内的脑损伤中的作用 阿尔茨海默病等疾病。 脑内ASS多肽的异常积聚和沉积可发生在 产量，但在大多数情况下，可能是由于中枢神经系统清除机制减少所致。净空 机制涉及促进Ass从中枢神经系统流出、介导Ass降解和/或 抑制ASS的组装和沉积。尽管已经发现了许多分子可以 影响Ass的体外组装和沉积我们对大脑中这些过程的理解 仍然不完整。在这方面，assPP的N-末端区域(assPP18-119)是一个高度结构化的 与天冬氨酸多肽结合并能抑制其组装的蛋白质区域。因此，总体上， 形成这一探索性R21建议的基础的假设是， 分泌的AsPP蛋白参与调节Ass水平、淀粉样蛋白的形成和 通过抑制ASS组装活性在大脑中沉积。 在本提案中，我们计划实施研究，以调查N-末端区域是如何 AsPP在体内与Ass多肽相互作用，调节其组装、沉积和病理变化 与这些过程相关的后果。对于这些研究，我们将利用两个不同的和良好的- 人ASS沉积的转基因小鼠特征模型及其增加途径 他们中的asspp N-末端片段水平，以了解sasspp的这个区域可能如何改变 病理结果。最后，这一新发现的sASPP活性，特别是N-末端 AssPP18-119片段，可能导致开发治疗药物的新途径 阿尔茨海默病及相关淀粉样蛋白中病理性ASS的堆积、聚集和沉积 寄生疾病。

Abnormal accumulation, assembly and deposition of the amyloid ss-protein (Ass) is a prominent pathological feature of patients with Alzheimer's disease (AD) and related disorders. Ass peptides are derived through sequential proteolytic processing of the Ass precursor protein (AssPP) by ss- and ¿- secretase activities. AssPP is highly expressed in brain although its physiological functions remain poorly understood. Many functional domains have been identified on secreted forms of AssPP proteins that could participate in variety of neuroprotective activities ranging from proteinase inhibition to ligand binding to cytoprotection. For example, during the previous funding period we unequivocally demonstrated that the Kunitz proteinase inhibitory (KPI) activity of sAssPP limits the extent of cerebral thrombosis. Additional protective activities are likely associated with other biologically active domains present on sAssPP proteins in response to cerebral injuries including chronic neurodegenerative disorders such as AD. The abnormal accumulation and deposition of cerebral Ass peptides can occur from increased production but in most cases is likely due to decreased clearance mechanisms in the CNS. Clearance mechanisms involve factors that can promote Ass efflux from the CNS, mediate Ass degradation, and/or inhibit Ass assembly and deposition. Although numerous molecules have been identified that can influence Ass assembly and deposition in vitro our present understanding of these processes in brain remains incomplete. In this regard, the N-terminal region of AssPP (AssPP18-119) is a highly structured region of the protein that binds to Ass peptides and can inhibit their assembly. Thus, the overall hypothesis that forms the basis of this exploratory R21 proposal is that the N-terminal region of secreted AssPP proteins contributes to the regulation of Ass levels, amyloid formation and deposition in brain through its Ass assembly inhibiting activities. In the present proposal we plan to implement studies to investigate how the N-terminal region of AssPP interacts with Ass peptides in vivo to regulate their assembly, deposition and the pathological consequences associated with these processes. For these studies we will utilize two distinct and well- characterized transgenic mouse models of human Ass deposition coupled with approaches to increase AssPP N-terminal fragment levels in them, to understand how this region of sAssPP might alter pathological outcomes. Finally, this newly identified activity of sAssPP, and in particular the N-terminal AssPP18-119 fragment, may lead to new approaches for developing therapeutic agents to combat pathological Ass accumulation, assembly and deposition that occurs in AD and related amyloid depositing diseases.