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β-蛋白（Ass）的异常积累、组装和沉积是一个突出的 阿尔茨海默病（AD）及相关疾病患者的病理学特征。屁股肽是 通过ss-和<$-对Ass前体蛋白（AssPP）进行连续蛋白水解加工而获得。 分泌酶活性。AssPP在脑中高度表达，但其生理功能仍然存在 不太了解。在分泌型的AssPP蛋白上已经鉴定出许多功能结构域 其可以参与多种神经保护活性，从蛋白酶抑制到配体 与细胞保护结合。例如，在上一个供资期间，我们明确表示， 表明sAssPP的Kunitz蛋白酶抑制（KPI）活性限制了脑缺血的程度。 血栓形成额外的保护活性可能与其他生物活性结构域相关 存在于sAssPP蛋白上，以响应脑损伤，包括慢性神经退行性疾病 疾病，如AD。 脑内Ass肽的异常积累和沉积可发生于 但在大多数情况下，可能是由于CNS中清除机制的降低。间隙 机制涉及可促进Ass从CNS流出、介导Ass降解和/或 抑制Ass组装和沉积。尽管已经鉴定出许多分子， 影响Ass在体外组装和沉积我们目前对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（AssPP 18 -119）是高度结构化的， 与Ass肽结合并可抑制其组装的蛋白质区域。因此， 形成这种探索性R21提议的基础的假设是， 分泌的AssPP蛋白有助于调节Ass水平、淀粉样蛋白形成和 在脑中的沉积通过其Ass组装抑制活性。 在目前的建议中，我们计划进行研究，以调查如何N-末端区域的 在体内，AsPP与Ass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，我们将利用两种不同且良好的- 人Ass沉积的表征的转基因小鼠模型， assPP N-末端片段水平，以了解sAssPP的这一区域如何改变 病理结果。最后，这种新鉴定的sAssPP活性，特别是N-末端 AssPP 18 -119片段，可能导致开发治疗药物的新方法，以对抗 AD和相关淀粉样蛋白中发生的病理性Ass积聚、装配和沉积 传播疾病。