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处理的两个亚单位PSEN1和PSEN2的突变会导致家族性阿尔茨海默病(FAD)。来自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这种联系。家族性丹麦痴呆(FDD)是一种类似AD的神经退行性疾病，由BRI2/ITM2b基因突变引起。有趣的是，BRI2是应用程序处理的抑制因素。引起FDD的突变导致BRI2功能丧失和APP处理增加。对一种在基因上与人类疾病一致的FDD动物模型(称为FDDKI，它像人类一样，携带一个野生型和一个突变的Bri2等位基因)的分析表明，BRI2中的FDD突变会导致突触可塑性受损和严重的海马体记忆障碍。在FDDKI/APP单倍体缺陷小鼠中可以看到这些缺陷的恢复。此外，抑制APP处理可以挽救FDDKI小鼠的突触缺陷，进一步将APP处理与家族性丹麦痴呆症联系起来。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”。如果得到证实，这一观点将代表着该领域在概念上的重大变化。在这里，我们将进一步描述丹麦BRI2突变和APP处理触发FDDKI突触和海马区记忆缺陷的机制。这些研究可能有助于阐明阿尔茨海默病的发病机制，并为治疗阿尔茨海默病的药物揭示新的靶点。

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.