Intersectin Links Amyloidogenic Processes in Alzheimer Disease and Down Syndrome

描述(申请人提供)：阿尔茨海默病(AD)困扰着我们老龄化的人口，是导致老年人认知障碍的最常见原因，也是美国第六大主要死亡原因。AD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小体增大。有趣的是，35岁以上的唐氏综合征(DS)患者总是会出现类似AD的神经病理，这表明这种AD变种是由21号染色体上与AD相关的基因三体引起的。AD病理的核心是编码在21号染色体上的淀粉样前体蛋白(APP)的异常加工。APP三重复制会产生部分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DS临界区(DSCR)的部分三体21足以在DS患者中产生AD。这些数据表明，除了APP，AD的发生还需要其他DSCR基因。支架蛋白Intersectin1位于DSCR上，在DS的mRNA和蛋白水平过表达，并在有和无AD诊断的DS患者脑中差异表达，这一事实使ITSN1成为一个强有力的候选基因。ITSN在促进AD致病APP处理的多个途径中增强神经退化和功能的能力加强了这一假说。ITSN1调节AD的两个主要过程：细胞内吞作用和c-Jun-N末端激酶(JNK)的激活。ITSN1调节内吞作用的多个方面，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APP的病理性加工和神经退行性变。因此，在DS和AD中，ITSN1的过度表达可能导致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ITSN1水平对APP加工的影响，(2)确定ITSN1调节的通路，如内吞和JNK信号，在APP加工中的作用，以及(3)确定ITSN1在利用新型转基因小鼠体内加工APP和淀粉样斑块形成过程中的贡献。作为第一个研究ITSN1在AD中作用的研究，这些实验将为早期内吞病理和APP处理的调控提供新的见解。这一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变性异常联系起来，并提供了在AD认知表现和经典组织病理学之前开发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.