BRI2 Familial British and Danish Dementias and Alzheimer's Disease

摘要阿尔茨海默病（Alzheimer's Disease， AD）是世界上最常见的老年痴呆原因，与大脑淀粉样斑块有关，淀粉样斑块主要由ß肽组成。这些肽是由淀粉样蛋白前体蛋白（APP）的双重裂解产生的。BACE1裂解产生c端片段ß-CTF，然后被γ-分泌酶加工成几个ase1亚型。遗传数据表明，APP加工的调控有助于AD，这促使我们对APP加工的调控进行遗传筛选。我们分离出在ad样家族性丹麦和英国痴呆（FDD和FBD）中发生突变的基因ITM2B/BRI2，发现它与APP紧密结合，并通过BACE1抑制APP的切割。为了解决APP加工的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小鼠由于BRI2功能丧失和BACE1对APP的加工增加而出现突触可塑性/记忆缺陷。然而，令人惊讶的是，我们发现ß-CTF而不是ß是这些小鼠中主要的突触毒性APP代谢物。对我们的观察最简单的解释是AD和FDD/FBD在病理上是不同的。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）突变形式的小鼠模型中，asas的致病性中心性已经被证明，因此人类asas，而我们的结果源于依赖内源性小鼠APP表达和APP处理调节因子缺失的模型系统。在这种情况下，值得注意的是，ITM2B/BRI2最近被确定为健康ApoE4携带者和不携带ApoE4等位基因的LOAD患者共有的基因表达模式的主要调节因子。这一证据在人类中确立了ITM2B/BRI2与AD最强遗传风险因子ApoE4以及ITM2B/BRI2与散发性AD之间的直接联系，支持了FDD和FBD是FAD遗传变异的观点。不管哪一种解释是正确的，有两点值得注意；1)抑制BACE1切割APP的治疗方法在所有情况下都是有效的；

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.