N-terminus of sAPP Regulates Abeta Assembly

sAPP 的 N 末端调控 Abeta 组装

• 批准号: 8619887
• 负责人: William E. Van Nostrand
• 金额: $ 19.69万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-25 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8619887
• 关键词: Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Amyloid deposition; Asses; Binding; Blood Vessels; Brain; Carotid Artery Thrombosis; Cause of Death; Cerebral Ischemia; Cerebral Thrombosis; Cerebral hemisphere hemorrhage; Cerebrum; Chronic; Country; Coupled; Cytoprotection; Deposition; Disease; Exons; Funding; Genes; Human; In Vitro; Injury; Lead; Ligand Binding; Light; Mediating; N-terminal; Nerve Degeneration; Neurodegenerative Disorders; Outcome; Pathology; Patients; Peptide Hydrolases; Peptides; Physiological; Process; Production; Property; Protease Inhibitor; Protein Binding; Protein Binding Domain; Protein Fragment; Protein Isoforms; Protein Precursors; Protein Region; Proteins; Proteolytic Processing; Regulation; Role; Severities; Staging; Structure; Therapeutic Agents; Thrombosis; Time; Transgenic Mice; amyloid formation; amyloid pathology; base; combat; in vivo; insight; mouse model; novel strategies; protein degradation; public health relevance; response; secretase

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.

淀粉样SS蛋白（ASS）的异常积累，组装和沉积是突出的 阿尔茨海默氏病（AD）和相关疾病患者的病理特征。屁股肽是 通过ss-和�-屁股前体蛋白（ASSPP）的顺序蛋白水解加工得出 分泌酶活动。 AssPP is highly expressed in brain although its physiological functions remain 理解不佳。在分泌的ASSPP蛋白上已经确定了许多功能域 可能参与从蛋白酶抑制到配体的各种神经保护活性 与细胞保护作用结合。例如，在上一个资金期间，我们明确地 证明SASSPP的Kunitz蛋白酶抑制（KPI）活性限制了脑的程度 血栓形成。其他受保护的活动可能与其他生物活性领域有关 响应于包括慢性神经退行性的脑损伤的SASSPP蛋白上存在 诸如AD之类的疾病。 大脑屁股宠物的异常积累和沉积可能是由于增加而发生的 生产，但在大多数情况下，可能是由于中枢神经系统中的清除机制降低所致。清除 机制涉及可以促进中枢神经系统流出的因素，介导屁股降解和/或 抑制屁股的组装和沉积。尽管已经发现了许多分子 影响屁股的组装并在体外沉积我们对这些过程中的当前理解 仍然不完整。在这方面，ASSPP的N末端区域（ASSPP18-119）是高度结构化的 结合屁股的蛋白质区域，可以抑制其组装。那，总体 构成此探索性R21提案的基础的假设是 分泌的ASSPP蛋白有助于调节屁股水平，淀粉样蛋白形成和 通过其屁股组装抑制活动中的大脑沉积。 在本提案中，我们计划实施研究，以研究 ASSPP与体内的ASS肽相互作用，以调节其组装，沉积和病理学 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良好 表征人类屁股沉积物的转基因小鼠模型以及增加的方法 其中的Asspp n末端碎片水平，以了解SASSPP的该区域如何改变 病理结果。最后，这种新确定的SASSPP活动，尤其是N端 ASSPP18-119片段，可能导致开发治疗剂对抗的新方法 AD和相关淀粉样蛋白发生的病理屁股积累，组装和沉积 沉积疾病。