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。AD的特征在于进行性痴呆和脑中存在β-淀粉样蛋白（A-β）斑块、神经元缠结和扩大的内体。有趣的是，35岁以上的唐氏综合征（DS）患者总是发展成AD样神经病理学，这表明AD的这种变体是由21号染色体上与AD相关的基因的三体性引起的。AD病理学的核心归因于淀粉样前体蛋白（APP）的异常加工，其在21号染色体上编码。APP三倍产生部分AD表型，但不足以产生定义AD的全部认知症状和神经病理学体征。相反，跨越DS关键区（DSCR）的部分21三体足以在DS患者中产生AD。这些数据表明，其他DSCR基因是必需的，除了APP，AD的发展。支架蛋白Intersectin 1位于DSCR上，在DS中在mRNA和蛋白质水平上过表达，并且在患有和没有诊断为AD的DS患者的大脑中差异表达，这一事实使ITSN 1成为一个强有力的候选者。ITSN增强神经退行性变的能力和在AD中促进致病APP加工的多个途径中的功能加强了这一假设。ITSN 1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。ITSN 1调节内吞作用的多个方面，这些方面对于APP的内化及其后续加工至关重要。ITSN还激活JNK，并且JNK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，ITSN 1的过表达可能导致APP内吞作用和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）确定调节ITSN 1水平对APP加工的影响，（2）确定ITSN 1调节的途径，如内吞作用和JNK信号传导，在APP加工中的作用，和（3）确定ITSN 1对APP的体内加工和淀粉样斑块形成的贡献。作为第一个研究ITSN 1在AD中的作用的研究，这些实验将提供新的见解APP加工的早期内吞病理和调节。该应用的独特方法将在AD和DS中观察到的亚临床内吞和淀粉样异常联系起来，并提供了在AD的认知表现和经典组织病理学之前的新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.