BR12 Familial British and Danish Dementias and Alzheimer's Disease

描述(申请人提供)：APP被？-和？-分泌酶连续切割产生A？在阿尔茨海默病(AD)中起致病作用的多肽，以及介导APP信号的AID/AICD。一些APP和β-分泌酶突变会改变A？常染色体显性遗传性家族性阿尔茨海默病(FAD)。鉴于APP处理在AD中的作用和APP介导的功能，APP裂解的调节剂，如BRI2，具有生物学意义和治疗意义。值得注意的是，BRI2突变导致两种类似AD的疾病：常染色体显性遗传性家族性英国痴呆(FBD)和家族性丹麦痴呆(FDD)。我们进一步研究了BRI2-APP相互作用的意义，发现：1)BRI2抑制APP加工和A2的产生；2)引起FBD和FDD的BRI2突变体对APP加工的抑制作用很差。因此，我们的工作假设是：A)BRI2是APP分泌酶切割的竞争性抑制剂；B)BRI2调节AD的发病；C)FBD和FDD BRI2突变加剧了AD的进展，APP加工异常可能参与了FDD和FBD的发病。这笔拨款有三个目的，我们建议用来检验这些假说。公共卫生相关性：阿尔茨海默病(AD)是世界上导致痴呆症的最常见原因。据估计，在60-年龄段的人中，约有1%的人患有阿尔茨海默病，85岁后，这一比例稳步上升至35%-40%。AD是由大脑中斑块的形成引起的。这些斑块损害神经细胞的功能，最终导致这些细胞死亡。当损害足够大时，痴呆症就会随之而来。这些衰老斑块是由一种小分子积累形成的。科学家和工业界的大部分努力都集中在发现能够防止这些斑块形成或促进这种有毒物质去除的药物上。本项目申请旨在研究一种可以减少这种有毒物质形成的蛋白质。我们希望我们的研究将转化为一个项目，开发改变疾病进程的药物，而不是像目前所有批准的治疗AD的药物那样简单地治疗症状。

DESCRIPTION (provided by applicant): Sequential cleavage of APP by ?- and ?-secretase yields A? peptides that are pathogenic in Alzheimer's Disease (AD), along with AID/AICD, which mediates APP signaling. Some APP and ? -secretase mutations alter the rate of A? production and cause autosomal dominant familial AD (FAD). Given the role of APP processing in AD and APP-mediated functions, modulators of APP cleavage such as BRI2 are biologically relevant and of therapeutic interest. Of note, BRI2 mutations cause autosomal dominant Familial British (FBD) and Familial Danish (FDD) Dementia two AD-like diseases. We have further studied the significance of the BRI2-APP interaction and found that: 1) BRI2 inhibits APP processing and A2 generation; 2) BRI2 mutants that cause FBD and FDD are poor inhibitors of APP processing. Thus, our working hypothesis is that: A) BRI2 is a competitive inhibitor of APP cleavage by secretases; B) BRI2 regulates AD pathogenesis; C) FBD and FDD BRI2 mutants exacerbate the progression of AD, and dis- regulation of APP processing may participate in FDD and FBD pathogenesis. This grant has three Aims in which we propose to test these hypotheses. PUBLIC HEALTH RELEVANCE: Alzheimer's disease (AD) is the most common cause of dementia in the world. It is estimated that ~1% of humans aged 60-64 years have AD, increasing steadily to as many as 35%-40% after age 85. AD is caused by the formation of plaques in the brain. These plaques impair the function of neuronal cells and, eventually, cause death of these cells. When the damage is large enough, dementia ensues. These senile plaques are formed by accumulation of a small molecule. Much of the efforts from scientists and industry are concentrated on findings drugs capable of preventing formation of these plaques or promoting the removal of this noxious material. This project application aims to study a protein that can diminish the formation of this toxic substance. We hope that our studies will translate into a program to develop drug for altering the course of the disease versus simply treating the symptoms like all of the approved drugs for AD currently are.