Altered APP metabolism triggers changes in tau that cause dementia

APP 代谢的改变会引发 tau 蛋白的变化，从而导致痴呆

• 批准号: 9323238
• 负责人: Tracy L YOUNG-PEARSE
• 金额: $ 26.63万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9323238
• 关键词: 12 year old; Active Sites; Address; Adult; Affect; Age-Years; Alzheimer' s Disease; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Apoptosis; Apoptotic; Attention; Autopsy; Binding; Biological Assay; Biological Markers; Brain region; C-terminal; Cell Death; Cell Line; Cells; Cerebrospinal Fluid; Chromosomes, Human, Pair 21; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Collection; Data; Dementia; Deposition; Detection; Diploidy; Disease; Down Syndrome; Elderly; Employee Strikes; Enzymes; Exhibits; Gene Proteins; Genes; Genetic; Human; Immunoassay; Individual; Inherited; Intellectual functioning disability; Length; Libraries; Life; Life Expectancy; Link; London; Longitudinal Studies; MAPT gene; Measures; Mediating; Microtubules; Molecular; Morphology; Mutation; Neurofibrillary Tangles; Neurons; Outcome; Pathogenicity; Pathology; Patients; Persons; Phenotype; Physically Handicapped; Physiological; Play; Presenile Alzheimer Dementia; Process; Production; Reporting; Rodent; Role; Sampling; Series; Staging; Symptoms; System; Technology; Testing; Time; base; brain cell; demented; experimental study; extracellular; familial Alzheimer disease; induced pluripotent stem cell; middle age; mild cognitive impairment; mutant; neuropathology; non-demented; novel; paired helical filament; presenilin-1; presenilin-2; protein metabolism; response; spatiotemporal; tau Proteins; tau mutation; tau-1; therapeutic target; tool; virtual

Rare inherited forms of disease often reveal important information about more common sporadic forms of the same disease, and this is true for Alzheimer's disease (AD). Typically, AD is a disease of the elderly, however, a collection of autosomal dominant familial forms of AD (fAD) strike in late-mid life, but are otherwise very similar to sporadic AD. All cases of fAD are attributable to mutations in one of three genes: APP, PSEN1 or PSEN2. APP encodes for the amyloid precursor protein (APP) and the PSEN genes encode the active site of an enzyme for which APP is a substrate. APP is located on chromosome 21 and all persons with Down's syndrome (DS) develop AD neuropathology by their 30-40s, and if they live long enough virtually all DS adults become demented. Triplication of all or part of chromosome 21 is the main cause of DS and also leads to an increased life-long production of APP. This persuasive genetic evidence indicates that APP plays a central role in at least some forms of AD. Several proteolytic fragments of APP are suggested to be pathogenic and although it is uncertain which of these initiate the AD cascade, there is widespread acceptance that the microtubule-associated protein tau is critical for the proliferation of the disease process. Burgeoning data suggest that tau can spread from neuron to neuron in a highly stereotypic manner that is tightly linked to the emergence of symptoms in AD. However, little is known about the molecular identity of extracellular tau or the processes by which it is released from cells. We recently discovered that a variety of tau species are released from both primary rodent cortical neurons and human iPSC-derived cortical neurons (iCNs). We hypothesize that tau species released from wild type neurons have a physiological function, whereas we anticipate that additional, pathogenic tau species will be released from DS and fAD neurons. Since fAD carriers and persons with DS are predetermined to develop AD, we will use patient-derived DS and fAD iCNs as tools to identify pathogenic forms of tau. This will involve comparison of media and lysates of iCNs from non-demented controls, iCNs from DS and fAD gene edited cell lines with diploid expression of wild type APP, and mutant iCNs. These analyses will employ a battery of novel immunoassays to investigate the molecular identity of tau species. Using a unique library of DS, MCI, AD, and non-demented control CSF samples, we will validate the disease-relevance of changes detected in our iCNs. Thereafter, we will test if predicted pathogenic forms of tau induce the apoptotic phenotype seen in older cultures of DS and wild type iCNs when applied extracellularly. Given our expertise in iPSC technology, sophisticated tau detection systems, and access to unique patient samples, we expect to identify new biomarkers and provide important information for therapeutic targeting of pathogenic forms of tau.

罕见的遗传形式的疾病通常揭示有关更常见的零星形式的重要信息 同样的疾病，对于阿尔茨海默氏病（AD）也是如此。通常，AD是老年人的疾病 在晚期生活中，一系列常染色体占主导地位的AD（FAD）罢工的集合，但否则非常 类似于零星的广告。所有时尚病例都归因于三个基因之一的突变：APP，PSEN1或 PSEN2。 APP编码淀粉样蛋白前体蛋白（APP）和PSEN基因编码 应用程序是基材的酶。应用位于21号染色体上，所有唐人 综合征（DS）以30-40的形式发展AD神经病理学，如果它们的寿命足够长，几乎所有DS成人 变得痴迷。全部或部分染色体21的一式三次是DS的主要原因，也导致 增加了应用程序生产的生产。这个有说服力的遗传证据表明，应用程序起着核心作用 至少在某些形式的广告中。建议APP的几个蛋白水解片段是致病性的， 尽管尚不确定其中哪一个启动了广告级联，但人们普遍认为 微管相关的蛋白质tau对于疾病过程的增殖至关重要。迅速的数据 建议Tau可以以高度刻板的方式从神经元传播到神经元，并紧密相关 AD症状的出现。但是，对于细胞外tau或 从细胞中释放它的过程。我们最近发现释放了各种tau物种 来自原发性啮齿动物皮质神经元和人IPSC衍生的皮质神经元（ICNS）。我们假设 从野生型神经元释放的tau物种具有生理功能，而我们预计 DS和FAD神经元将释放其他致病性TAU物种。由于时尚的载体和人员 使用DS进行预先确定以开发AD，我们将使用患者来源的DS和FAD ICN作为识别的工具 tau的致病形式。这将涉及比较非序列的ICN的培养基和裂解物 来自DS的对照，ICN和FAD基因编辑的细胞系具有野生型应用的二倍体表达和突变体 ICNS。这些分析将采用一系列新型免疫测定来研究TAU的分子身份 物种。使用独特的DS，MCI，AD和非痴呆的对照CSF样品库，我们将验证 在我们的ICN中检测到的变化的疾病率。此后，我们将测试是否预测的致病形式 细胞外应用时，诱导DS和野生型ICN培养物中看到的凋亡表型。 鉴于我们在IPSC技术，复杂的TAU检测系统方面的专业知识，并获得了独特的患者的访问 样本，我们希望确定新的生物标志物，并为治疗靶向提供重要信息 tau的致病形式。