BRI2 Familial British and Danish Dementias and Alzheimer's Disease

描述(申请人提供)：阿尔茨海默病(AD)是世界上最常见的老年性痴呆的原因，与大脑淀粉样斑块有关，主要由A？多肽组成。这些多肽是由淀粉样前体蛋白(APP)的双裂解产生的。BACE1裂解产生C-末端片段-Ctf，该片段被γ-分泌酶加工成几种A？亚型。遗传数据表明，APP处理的调节有助于AD，这导致我们为APP处理的调节进行遗传筛选。我们分离了在类AD家族性丹麦和英国痴呆(FDD和FBD)中突变的ITM2B/BRI2基因，发现它与APP紧密结合，并抑制BACE1对APP的切割。为了解决APP处理过程改变参与痴呆症的假设，我们建立了丹麦和英国痴呆症的敲入模型。这些FDDKI和FBDKI小鼠表现出突触可塑性/记忆缺陷，这是由于BRI2功能的丧失和BACE1对APP处理的增加。然而，令人惊讶的是，我们发现在这些小鼠中，主要的突触毒性APP代谢物是？CTF而不是A？对我们观察到的最简单的解释是AD和FDD/FBD在病因学上是不同的。或者，我们的观察可能反映了我们使用的模型系统。在过度表达人类AD相关基因(APP和PS)的突变形式的小鼠模型中，以及人类Aü的致病中心性已经被证明，而我们的结果源于依赖内源性小鼠APP表达的模型系统，该模型系统伴随着APP处理调节因子的丧失。在这种背景下，重要的是要注意到，ITM2B/BRI2最近被确定为健康的ApoE4携带者和不携带ApoE4等位基因的LOAD患者共有的常见基因表达模式的主要调节因子。这一证据在人类中建立了ITM2B/BRI2和ApoE4之间的直接联系，ApoE4是AD的最强遗传风险因子，以及ITM2B/BRI2和散发性AD，支持FDD和FBD是FAD的基因变体的观点。无论哪种解释是正确的，有两点值得注意：1)抑制APP的BACE1裂解的治疗方法在所有情况下都是有效的； 2)γ-分泌酶抑制是治疗AD的一种积极的治疗方法，它会导致β-CTF的积聚，因此确定这种中间产物是否参与了AD的发病是至关重要的。 在本应用程序中，我们将进一步描述APP处理调节内存不足的机制。这些研究可能有助于阐明阿尔茨海默病的发病机制，并为治疗阿尔茨海默病的药物揭示新的靶点。

DESCRIPTION (provided by applicant): Abstract Alzheimer's Disease (AD) is the most common cause of ageing-dependent dementia in the world and is associated with cerebral amyloid plaques, mostly composed of Aß peptides. These peptides are produced by a double cleavage of the amyloid precursor protein (APP). BACE1 cleavage produces the C-terminal fragment, ß-CTF, which is then processed into several Aß isoforms by γ-secretase. Genetic data suggest that regulation of APP processing contributes to AD, which lead us to perform genetic screens for regulators of APP processing. We isolated ITM2B/BRI2, a gene mutated in AD-like familial Danish and British dementias (FDD and FBD), and found that it tightly binds APP and inhibits its cleavage by BACE1. To address the hypothesis that alterations of APP processing participate in dementia we generated knock-in models of Danish and British dementias. These FDDKI and FBDKI mice showed synaptic plasticity/memory deficits due to loss of BRI2 function and increased processing of APP by BACE1. Surprisingly however, we found that ß-CTF and not Aß, is the main synaptotoxic APP metabolite in these mice. The simplest explanation of our observations is that AD and FDD/FBD are pathogenically different. Alternatively, our observation may reflect the model systems we use. The pathogenic centrality of Aß has been shown in mouse models over-expressing mutant forms of human AD-associated genes (APP and PS) and thus human Aß, whereas our results stem from model systems that rely on endogenous, murine APP expression coupled to loss of an APP processing regulator. In this context, it is important to note that ITM2B/BRI2 has been recently identified as a master regulator of the common patterns of gene expression shared by healthy ApoE4 carriers and LOAD patients who do not carry the ApoE4 allele. This evidence establishes a direct connection in humans between ITM2B/BRI2 and ApoE4, the strongest genetic risk factor for AD, as well as ITM2B/BRI2 and sporadic AD, supporting the idea that FDD and FBD are genetic variants of FAD. Regardless of which explanation is correct, two points are worth noting; 1) a therapeutic approach inhibiting BACE1 cleavage of APP would be efficacious in all scenarios; 2) γ-secretase inhibition, an aggressively sought-after therapeutic approach for AD, would result in accumulation of ß-CTF so it is vital to determine if this intermediate contributes to pathogenesis. In this application, we will further characterize the mechanisms by which APP processing mediates memory deficit. These studies are likely to shed light on the pathogenesis of AD, as well as to unveil novel targets for disease-modifying AD drugs.