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

描述（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本身和调节APP加工的酶的两个亚基PSEN 1和PSEN 2的突变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处理和痴呆症之间的联系。家族性丹麦痴呆（Familial Danish Dementia，FDD）是一种AD样神经退行性疾病，由BRI 2/ITM 2b基因突变引起。有趣的是，BRI 2是APP加工的抑制剂。引起FDD的突变导致BRI 2功能的丧失和APP加工的增加。对遗传上与人类疾病一致的FDD动物模型（称为FDDKI，其与人类病例一样携带一个野生型和一个突变的Bri 2等位基因）的分析表明，BRI 2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单倍缺陷小鼠中观察到从这些缺陷的恢复。此外，APP加工的抑制挽救了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，与目前推动痴呆症研究的教条相反，sAPP和/或<$-CTF而不是A <$是主要的“有毒APP代谢物”。如果得到确认，这一观点将代表该领域的一个重大概念变化。在这里，我们将进一步表征丹麦BRI 2突变和APP处理触发FDDKI中突触和海马记忆缺陷的机制。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。

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.