BRI2 Familial British and Danish Dementias and Alzheimer's Disease

BRI2 英国和丹麦家族性痴呆症和阿尔茨海默病

• 批准号: 8831364
• 负责人: LUCIANO D'ADAMIO
• 金额: $ 31.83万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-15 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8831364
• 关键词: Address; Adult; Affect; Alleles; Alzheimer' s Disease; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Behavioral; Binding; Biological Models; Brain; British; C-terminal; Cerebrum; Complex; Coupled; Data; Dementia; Deposition; Development; Disease; Enzymes; Event; Familial Dementias; Functional disorder; Gene Expression Profile; Genes; Genetic; Genetic Screening; Health; Human; Knock-in Mouse; Lead; Learning; Light; Mediating; Memory; Memory Loss; Memory impairment; Mind; Modeling; Morphologic artifacts; Mus; Mutate; Mutation; Nerve Degeneration; Neurons; Pathogenesis; Patients; Peptide Hydrolases; Peptides; Pharmaceutical Preparations; Plant Roots; Play; Process; Protein Isoforms; Proteins; Proteomics; Publishing; Regulation; Role; Senile Plaques; Staging; Synapses; Synaptic plasticity; System; Testing; Therapeutic; Therapeutic Intervention; Toxic effect; age related; amyloid precursor protein processing; apolipoprotein E-4; beta-site APP cleaving enzyme 1; familial Alzheimer disease; genetic risk factor; genetic variant; inhibitor/antagonist; insight; mouse model; mutant; neurotoxic; novel; presenilin; prevent; protein expression; protein metabolism; protein metabolite; reconstitution; research study; secretase; stem

DESCRIPTION (provided by applicant): 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 Aβ peptides. These peptides are produced by a double cleavage of the amyloid precursor protein (APP). BACE1 cleavage produces the C-terminal fragment, β-CTF, which is then processed into several Aβ 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 β-CTF and not Aβ,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 Aβ has been shown in mouse models over-expressing mutant forms of human AD-associated genes (APP and PS) and thus human Aβ, 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 β-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.

描述（由申请人提供）：阿尔茨海默病（AD）是世界上年龄依赖性痴呆的最常见原因，与大脑淀粉样斑块相关，主要由Aβ肽组成。这些肽是由淀粉样前体蛋白（APP）的双重切割产生的。BACE 1裂解产生C-末端片段β-CTF，然后通过γ-分泌酶加工成几种Aβ亚型。遗传数据表明，APP处理的调节有助于AD，这促使我们对APP处理的调节因子进行遗传筛查。我们分离了ITM 2B/BRI 2，一个在AD样家族性丹麦和英国痴呆（FDD和FBD）中突变的基因，发现它与APP紧密结合，并抑制BACE 1对其的切割。为了解决这一假设，即APP处理的改变参与痴呆症，我们产生了丹麦和英国痴呆症的敲入模型。这些FDDKI和FBDKI小鼠由于BRI 2功能丧失和BACE 1对APP的加工增加而显示出突触可塑性/记忆缺陷。然而，令人惊讶的是，我们发现β-CTF而不是Aβ是这些小鼠中主要的突触毒性APP代谢物。我们的观察结果的最简单的解释是，AD和FDD/FBD是不同的病理。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AD相关基因（APP和PS）突变形式和人Aβ的小鼠模型中，已经显示了Aβ的致病中心性，而我们的结果来自依赖于内源性鼠APP表达和APP加工调节因子缺失的模型系统。在这种情况下，重要的是要注意，ITM 2B/BRI 2最近已被鉴定为健康ApoE 4携带者和不携带ApoE 4等位基因的LOAD患者所共有的基因表达的共同模式的主调节因子。这一证据在人类中确立了ITM 2B/BRI 2和ApoE 4（AD的最强遗传风险因素）之间的直接联系，以及ITM 2B/BRI 2和散发性AD之间的直接联系，支持FDD和FBD是FAD的遗传变异体的观点。无论哪种解释是正确的，有两点值得注意：1）抑制APP的BACE 1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，一种积极寻求的AD治疗方法，将导致β-CTF的积累，因此确定该中间体是否有助于发病机制至关重要。 在本申请中，我们将进一步描述APP处理介导记忆缺陷的机制。这些研究可能揭示AD的发病机制，并揭示疾病修饰AD药物的新靶点。