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或负责加工APP的酶的突变会导致家族性阿尔茨海默病。由于APP在生物学和病理学上的重要性，了解APP裂解是如何被控制的具有重要意义。抑制APP的处理可能会为AD的治疗干预提供解决方案。我们推测存在与APP结合并调节其加工的膜蛋白，并确定BRI2为APP配体。值得注意的是，BRI2突变导致英国和丹麦家族性痴呆(FBD和FDD)，这是两种AD样神经退行性疾病。成熟的BRI2抑制APP的加工和A2的产生，有趣的是，导致FDD的BRI2突变有成熟缺陷。这些发现促使我们假设BRI2调节和/或修改AD的发病机制，并且BRI2 FDD突变在体内是无效的A2生成抑制物。这最后一点提示APP加工的异常可能参与了FDD和FBD的发病。为了验证这些假设，我们创建了Bri2缺失的小鼠，以及FDD(FDDKI)的小鼠敲入(Ki)模型，该模型在遗传上是一致的，携带一个野生型和一个突变的Bri2等位基因，以人类为例。我们的数据显示，FDDKI小鼠在突触可塑性和严重的海马区记忆缺陷方面存在损害。在APP单倍体缺陷的FDDKI小鼠中，可以看到这些缺陷的恢复。Bri2杂合子小鼠表现出与FDDKI小鼠相似的记忆和突触可塑性缺陷，使我们认为这是一种功能突变，功能丧失是BRI2抑制APP的处理。我们还发现，BRI2驱动的多肽特异性地结合和抑制APP的处理，并可以挽救在FDDKI和一个流行的AD转基因小鼠模型(APPtg2575)中发现的突触缺陷。在这里，我们希望进一步研究FDDKI和Bri2杂合子小鼠的突触和海马区记忆缺陷，以阐明AD的发病机制，并在体内测试Bri2衍生的多肽作为一种可能的AD治疗干预措施。 公共卫生相关性： BRI2调节APP的加工，而不影响2-、1-或3-分泌酶的活性。我们的初步数据表明，致病的BRI2突变，导致类似AD的家族性痴呆，降低了BRI2的抗APP处理活性。这会导致我们的小鼠失去Bri2功能，从而导致海马体和突触可塑性缺陷。在本申请中：1)我们将继续确认FDD是由于BRI2功能(该功能是APP处理的抑制)的损失造成的。2)我们将研究导致FDDKI和Bri2小鼠记忆和突触可塑性缺陷的机制。3)我们将看看是否可以使用Bri2衍生的多肽作为治疗方法来治疗在痴呆小鼠模型中发现的记忆缺陷。FDDKI小鼠是基因上与人类疾病一致的唯一痴呆症模型。由于其与人类病理学的遗传保真度，FDDKI小鼠在剖析包括AD在内的人类痴呆的致病机制和测试治疗方法方面都起到了重要作用。此外，剖析BRI2的生理和病理作用及其与APP加工抑制活性的关系，将验证针对BRI2并能够减少APP加工的化合物的开发。这些化合物(如N3-2A)将是特异的(和有效的)AD药物，可以减少APP的处理，而不会干扰其他底物上的2-或3-分泌酶活性。相反，分泌酶抑制剂阻止所有分泌酶底物的切割，从而产生毒性效应，可能限制其治疗用途。这是一个紧迫的问题，因为分泌物有许多生物上重要的底物。因此，研究N3-2A对痴呆模型小鼠记忆障碍的改善作用，对于AD和其他痴呆的治疗干预具有重要意义。

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.