Dementia due to mutations in BRI2; link to Alzheimer's Disease

描述（由申请人提供）： 阿尔茨海默病（AD）的发病机制与淀粉样前体蛋白（APP）的加工密切相关，因为APP或负责其加工的酶的突变导致家族性阿尔茨海默病。由于其生物学和病理学的重要性，了解APP裂解是如何控制的是非常相关的。抑制APP加工可能为AD的治疗干预提供解决方案。我们假设存在结合APP并调节其加工的膜蛋白，并将BRI 2鉴定为APP配体。值得注意的是，BRI 2突变导致家族性英国和丹麦痴呆症（FBD和FDD），这是两种AD样神经退行性疾病。成熟的BRI 2抑制APP加工和A2产生，有趣的是，引起FDD的BRI 2突变体在成熟方面有缺陷。这些发现促使我们假设BRI 2调节和/或修饰AD发病机制，并且BRI 2 FDD突变体是体内A2生成的无效抑制剂。这最后一点提示APP加工的失调可能参与FDD和FBD的发病机制。为了检验这些假设，我们已经建立了Bri 2-null小鼠和FDD（FDDKI）的小鼠敲入（KI）模型，其与人类病例在遗传上一致，携带一个野生型和一个突变Bri 2等位基因。我们的数据表明，FDDKI小鼠有突触可塑性和严重的海马记忆缺陷的损害。从这些缺陷的恢复见于APP单倍缺陷的FDDKI小鼠中。Bri 2杂合小鼠显示出与FDDKI小鼠相似的记忆和突触可塑性缺陷，使我们相信这是功能缺失突变，功能缺失是BRI 2对APP加工的抑制。我们还发现，BRI 2驱动的肽特异性结合并抑制APP加工，并且可以挽救在FDDKI和流行的AD转基因小鼠模型（APPtg 2575）中发现的突触缺陷。在这里，我们希望进一步表征FDDKI和Bri 2杂合小鼠中的突触和海马记忆缺陷，以阐明AD的发病机制，并在体内测试Bri 2衍生肽作为AD的可能治疗干预。 公共卫生相关性： BRI 2调节APP加工而不影响2-、1-或3-分泌酶的活性。我们的初步数据表明，致病性BRI 2突变，导致类似于AD的家族性痴呆，降低了BRI 2的抗APP加工活性。这通过我们小鼠中Bri 2功能的丧失导致海马和突触可塑性缺陷。在本申请中：1）我们将继续确认FDD是由BRI 2功能（该功能是APP处理的抑制）丢失引起的。2)我们将研究导致FDDKI和Bri 2小鼠记忆和突触可塑性缺陷的机制。3)我们将看看我们是否可以使用Bri 2衍生的肽作为治疗痴呆小鼠模型中发现的记忆缺陷的治疗方法。FDDKI小鼠是唯一与人类疾病遗传一致的痴呆模型。由于它们与人类病理学的遗传保真度，FDDKI小鼠在解剖人类痴呆症（包括AD）的致病机制和测试治疗方面都是有用的。此外，剖析BRI 2的生理和病理作用及其与APP加工抑制活性的关系将验证靶向BRI 2并能够减少APP加工的化合物的开发。这些化合物（例如N3-2A）将是特异性（和有效的）AD药物，其将减少APP加工而不干扰2-或3-分泌酶对其它底物的活性。相反，分泌酶抑制剂阻断分泌酶的所有底物的裂解，从而产生可能限制其治疗有用性的毒性作用。这是一个紧迫的问题，因为分泌酶有许多生物学上重要的底物。因此，研究N3-2A在减轻痴呆小鼠模型中的记忆缺陷中的有效性在对AD和其他痴呆的治疗干预中可能是非常重要的。

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) pathogenesis is firmly associated with the processing of the amyloid precursor protein (APP), since mutations in APP or in the enzymes responsible for its processing cause Familial Alzheimer's disease. Because of its biological and pathological importance, understanding how APP cleavage is controlled is of great relevance. Inhibition of APP processing may possibly hold the solution for therapeutic intervention in AD. We postulated the existence of membrane proteins that bind APP and regulate its processing and have identified BRI2 as an APP ligand. Of note, BRI2 mutations cause Familial British and Danish Dementia (FBD and FDD), two AD-like neurodegenerative disorders. Mature BRI2 inhibits APP processing and A2 production and, interestingly, BRI2 mutants that cause FDD have a defect in maturation. These findings prompted us to hypothesize that BRI2 regulates and/or modifies AD pathogenesis and that BRI2 FDD mutants are ineffective inhibitors of A2 generation in vivo. This last point hints to the possibility that dis-regulation of APP processing may participate in the pathogenesis of FDD and FBD. To test these hypothesis, we have created Bri2-null mice, and a mouse knock-in (KI) models of FDD (FDDKI), which is genetically congruous, carrying one wild-type and one mutant Bri2 allele, to the human cases. Our data shows that FDDKI mice have an impairment in synaptic plasticity and severe hippocampal memory deficits. Recovery from these defects is seen in FDDKI mice haplodeficient for APP. Bri2 heterozygous mice show similar memory and synaptic plasticity defects as FDDKI mice, leading us to believe this is a loss of function mutation, with the function lost being the inhibition of processing of APP by BRI2. We have also found that a BRI2-drived peptide binds and inhibits APP processing specifically, and can rescue the synaptic deficits found in the FDDKI and a popular transgenic mouse model of AD (APPtg2575). Here, we hope to further characterize the synaptic and hippocampal memory deficits in FDDKI and Bri2 heterozygous mice to shed light on the pathogenesis of AD, as well as test the Bri2-derived peptide in vivo as a possible therapeutic intervention for AD. PUBLIC HEALTH RELEVANCE: BRI2 regulates APP processing without affecting the activity of either 2-, 1- or 3-secretases. Our preliminary data indicate that pathogenic BRI2 mutations, which cause familial dementias similar to AD, reduce the anti-APP processing activity of BRI2. This leads to hippocampal and synaptic plasticity defects through a loss of Bri2 function in our mice. In this application: 1) We will continue confirming that FDD is caused by a loss if BRI2 function (the function being the inhibition of APP processing). 2) We will study mechanisms that cause the memory and synaptic plasticity deficits in the FDDKI and Bri2 mice. 3) We will see if we can use a Bri2-derived peptide as a therapeutic approach in treating the memory deficits found in mouse models of dementias. The FDDKI mice are the only models of dementia genetically congruous to the human diseases. Because of their genetic fidelity with the human pathologies, FDDKI mice are instrumental in both dissecting the pathogenic mechanisms and testing therapies for human dementias, including AD. In addition, dissecting the physiological and pathological role of BRI2 and its relationship to the APP processing inhibitory activity would validate the development of compounds targeting BRI2 and capable of reducing APP processing. These compounds (e.g. N3-2A) would be specific (and effective) AD drugs that would reduce APP processing without interfering with either 2- or 3-secretase activity on other substrates. On the contrary, secretase inhibitors block cleavage of all substrates of secretases, thereby exerting toxic effects that may limit their therapeutic usefulness. This is a pressing problem since secretases have many biologically important substrates. Thus, studying the effectiveness of N3-2A in alleviating the memory deficits in mouse models of dementias could be of great importance in a therapeutic intervention to AD and other dementias.