Dissecting APP-mediated memory deficits in Danish dementia knock-in mice

描述（由申请人提供）：淀粉样前体蛋白（APP）的加工与阿尔茨海默病（AD）的发病机制密切相关。事实上，APP本身以及一种调节APP加工的酶的两个亚基PSEN1和PSEN2的突变会导致家族性阿尔茨海默病（FAD）。我们实验室的新证据进一步强调了APP处理与痴呆之间的联系。家族性丹麦痴呆（FDD）是一种ad样神经退行性疾病，是由BRI2/ITM2b基因突变引起的。有趣的是，BRI2是APP加工的抑制剂。引起FDD的突变导致BRI2功能丧失和APP加工增加。对与人类疾病遗传一致的FDD动物模型（称为FDDKI，与人类病例一样，携带一个野生型和一个突变型BRI2等位基因）的分析表明，BRI2中的FDD突变导致突触可塑性受损和严重的海马记忆缺陷。在FDDKI/APP单倍缺陷小鼠中可以看到这些缺陷的恢复。此外，APP加工的抑制可以修复FDDKI小鼠的突触缺陷，进一步将APP加工与家族性丹麦痴呆联系起来。有趣的是，我们的初步数据表明，与目前推动痴呆研究的教条相反，sAPP¿和/或¿-CTF而不是A¿是主要的“有毒APP代谢物”。如果得到证实，这一观点将代表该领域概念上的重大变化。在这里，我们将进一步表征丹麦BRI2突变和APP加工触发FDDKI突触和海马记忆缺陷的机制。这些研究有可能揭示阿尔茨海默病的发病机制，并揭示阿尔茨海默病药物的新靶点。

DESCRIPTION (provided by applicant): Processing of the amyloid precursor protein (APP) is firmly associated with the pathogenesis of Alzheimer's disease (AD). In fact, mutations in APP itself and in two subunits of an enzyme that regulates APP processing, PSEN1 and PSEN2, cause Familial Alzheimer's disease (FAD). New evidence from our laboratory further stress this link between APP processing and dementia. Familial Danish Dementia (FDD), an AD-like neurodegenerative disorders, is due to mutation in the BRI2/ITM2b gene. Interestingly, BRI2 is an inhibitor of APP processing. The mutations causing FDD results in a loss of BRI2 function and increased processing of APP. Analysis of an animal model of FDD genetically congruous to the human disease (called FDDKI, which, like the human cases, carries one wild-type and one mutant Bri2 allele), shows that the FDD mutation in BRI2 causes impairment in synaptic plasticity and severe hippocampal memory deficits. Recovery from these defects is seen in FDDKI/APP haplodeficient mice. In addition, inhibition of APP processing rescues the synaptic deficits of FDDKI mice, further connecting APP processing and Familial Danish dementia. Interestingly, our preliminary data suggest that, contrary to the current dogma driving the research in dementia, sAPP¿ and/or ¿-CTF rather than A¿, are the main "toxic APP metabolites". If confirmed, this view would represent a significant conceptual change for the field. Here, we will further characterize the mechanisms by which the Danish BRI2 mutation and APP processing trigger synaptic and hippocampal memory deficits in FDDKI. These studies are likely to shed light on the pathogenesis of AD, as well as to unveil novel targets for disease-modifying AD drugs. PUBLIC HEALTH RELEVANCE: Mutations in genes that regulate the processing of APP cause Familial Dementias in humans. BRI2 is one of these genes. We have generated a mouse model that faithfully represents the human dementias caused by the mutation in BRI2. In this model APP processing is increased and causes memory loss. Given the fact that these mice reproduce accurately the genetic defects of patients, they are ideal to dissect the pathogenic mechanisms that cause dementia in humans. Therefore, this model is suitable for testing therapies for human dementias, including Alzheimer's disease. The studies proposed in this grant application will also serve as a conceptual foundation to development BRI2-like drugs that reduce APP processing without inhibiting the enzymes that mediate processing of APP.