Intersectin Links Amyloidogenic Processes in Alzheimer Disease and Down Syndrome

描述（由申请人提供）：阿尔茨海默病（AD）困扰着我们的老龄化人口，是老年人认知障碍的最常见原因，也是美国第六大死亡原因。阿尔茨海默病的特征是进行性痴呆，大脑中存在β -淀粉样蛋白（a- β）斑块、神经原纤维缠结和内体增大。有趣的是，35岁以上的唐氏综合征（DS）患者总是会出现AD样神经病理，这表明这种AD变体是由21号染色体上与AD相关的基因三体引起的。AD病理的核心是淀粉样前体蛋白（APP）的异常加工，该蛋白编码在21号染色体上。APP三次复制产生部分AD表型，但不足以产生定义AD的全部认知症状和神经病理体征。相反，跨越退行性椎体滑移关键区（DSCR）的部分21三体足以在退行性椎体滑移患者中产生AD。这些数据表明，除了APP之外，AD的发展还需要其他DSCR基因。支架蛋白Intersectin1位于DSCR上，在DS中mRNA和蛋白水平过表达，并且在患有和未诊断为AD的DS患者的大脑中差异表达，这一事实使ITSN1成为一个强有力的候选。ITSN在促进AD致病性APP加工的多种途径中增强神经变性和功能的能力加强了这一假设。ITSN1调节AD中紊乱的两个主要过程：内吞作用和c- jun - n末端激酶（JNK）激活。ITSN1调控胞吞作用的多个方面，这些方面对APP的内化及其后续加工至关重要。ITSN还激活JNK， JNK的激活进一步促进致病性APP加工和神经变性。因此，在DS和AD中，ITSN1的过表达可能导致APP内吞和JNK激活增加，从而增加神经毒性APP裂解产物的产生。本研究将(1)确定ITSN1水平调节对APP加工的影响，(2)确定ITSN1调控的途径，如内吞作用和JNK信号通路在APP加工中的作用，以及(3)利用新型转基因小鼠确定ITSN1对APP和淀粉样斑块形成的体内加工的贡献。作为第一个研究ITSN1在AD中的作用的研究，这些实验将为APP加工的早期内吞病理和调控提供新的见解。该应用的独特方法将AD和DS中观察到的亚临床内吞和淀粉样变性异常联系起来，并提供了在AD的认知表现和经典组织病理学之前发现新的生物标志物和治疗靶点的可能性。

DESCRIPTION (provided by applicant): Alzheimer Disease (AD) plagues our ageing population as the most common cause of cognitive impairment in the elderly and the sixth leading cause of death in America. AD is characterized by progressive dementia and the presence of beta-amyloid (A-beta) plaques, neurofibrillary tangles, and enlarged endosomes in the brain. Interestingly, Down Syndrome (DS) patients over the age of 35 invariably develop AD-like neuropathology, suggesting that this variant of AD is caused by trisomy of genes related to AD on chromosome 21. The core of AD pathology is attributed to aberrant processing of Amyloid Precursor Protein (APP), which is encoded on chromosome 21. APP triplication produces a partial AD phenotype, but is not sufficient to produce the full spectrum of cognitive symptoms and neuropathologic signs that define AD. In contrast, partial trisomy 21 spanning the DS critical region (DSCR) is sufficient to produce AD in DS patients. These data suggest that other DSCR genes are required, in addition to APP, for the development of AD. The fact that the scaffold protein Intersectin1 is located on the DSCR, overexpressed at the mRNA and protein level in DS, and differentially expressed in the brains of DS patients with and without a diagnosis of AD makes ITSN1 a strong candidate. This hypothesis is strengthened by ITSN's ability to enhance neurodegeneration and function in multiple pathways that promote pathogenic APP processing in AD. ITSN1 regulates two major processes that are deranged in AD: endocytosis and the c-Jun-N-terminal kinase (JNK) activation. ITSN1 regulates multiple aspects of endocytosis that are critical for the internalization of APP and its subsequent processing. ITSN also activates JNK and JNK activation further contributes to pathogenic APP processing and neurodegeneration. Thus, in DS and AD the overexpression of ITSN1 may result in increased APP endocytosis and JNK activation, thereby increasing the production of neurotoxic APP cleavage products. This research will (1) determine the effect of modulating ITSN1 levels on APP processing, (2) determine the role of ITSN1-regulated pathways, such as endocytosis and JNK signaling, in APP processing, and (3) determine the contribution of ITSN1 to in vivo processing of APP & amyloid plaque formation using novel transgenic mice. As the first study to investigate the role of ITSN1 in AD, these experiments will provide novel insight into the early endocytic pathology and regulation of APP processing. The unique approach of this application links the subclinical endocytic and amyloidogenic anomalies observed in AD and DS and offers the possibility of new biomarkers and therapeutic targets that precede the cognitive manifestations and classic histopathology of AD. PUBLIC HEALTH RELEVANCE: Endocytic abnormalities are now recognized as the earliest manifestation of Alzheimer Disease, preceding the development of cognitive symptoms. Our work investigates the role of a scaffold protein, intersectin1, in the etiology of this preclinical pathology. Understanding the role of intersectin1-regulated pathways in this disease process will aid in the potential development of preventative and therapeutic technologies.