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

基本信息

批准号：
9166179
负责人：
Tracy L YOUNG-PEARSE
金额：
$ 22.19万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
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/9166179
关键词：
12 year old Active Sites Address Adult Affect Age-Years Alzheimer&apos 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 Genes Genetic Human Immunoassay Individual Inherited Intellectual functioning disability Length Libraries Life Life Expectancy Link London Longitudinal Studies MAPT gene Measures Mediating Microtubules Molecular Mutation Neurofibrillary Tangles Neurons Outcome 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 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 research study response spatiotemporal tau Proteins tau mutation tau-1 therapeutic target tool

项目摘要

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.

罕见的遗传性疾病常常揭示有关更常见的散发性疾病的重要信息同样的疾病，阿尔茨海默病（AD）也是如此。通常，AD 是一种老年人疾病，但是，常染色体显性家族性 AD (fAD) 的集合，发病于中年晚期，但在其他方面非常严重类似于散发性AD。所有 fAD 病例均可归因于以下三个基因之一的突变：APP、PSEN1 或 PSEN2。 APP 编码淀粉样前体蛋白 (APP)，PSEN 基因编码其活性位点以 APP 为底物的酶。 APP 位于 21 号染色体上，所有唐氏综合症患者综合症 (DS) 在 30-40 多岁时就会出现 AD 神经病理学，如果他们活得足够长，几乎所有 DS 成年人都会出现 AD 神经病理学症状变得疯狂。 21 号染色体全部或部分三倍体是 DS 的主要原因，也会导致增加 APP 的终身产量。这种有说服力的遗传证据表明 APP 发挥着核心作用至少在某些形式的 AD 中。 APP 的几个蛋白水解片段被认为是致病性的并且尽管不确定哪一个会引发 AD 级联反应，但人们普遍认为微管相关蛋白 tau 对于疾病过程的增殖至关重要。数据激增表明 tau 蛋白可以以高度刻板的方式从一个神经元传播到另一个神经元，这种方式与 AD症状的出现。然而，人们对细胞外 tau 蛋白或细胞外 tau 蛋白的分子身份知之甚少。它从细胞中释放的过程。我们最近发现多种 tau 蛋白被释放来自原代啮齿动物皮层神经元和人类 iPSC 衍生的皮层神经元 (iCN)。我们假设从野生型神经元释放的 tau 蛋白具有生理功能，而我们预计另外，致病性 tau 蛋白会从 DS 和 fAD 神经元中释放出来。由于 fAD 携带者和个人 DS 被预先确定为发展 AD，我们将使用患者衍生的 DS 和 fAD iCN 作为工具来识别 tau 蛋白的致病形式。这将涉及来自非痴呆的 iCN 的培养基和裂解物的比较对照、来自 DS 和 fAD 基因编辑细胞系的 iCN（具有野生型 APP 的二倍体表达）和突变体 iCN。这些分析将采用一系列新型免疫分析来研究 tau 分子的身份物种。使用独特的 DS、MCI、AD 和非痴呆对照 CSF 样本库，我们将验证我们的 iCN 中检测到的变化与疾病的相关性。此后，我们将测试预测的 tau 蛋白致病形式是否当应用于细胞外时，诱导 DS 和野生型 iCN 的旧培养物中观察到的细胞凋亡表型。鉴于我们在 iPSC 技术、先进的 tau 检测系统和独特患者方面的专业知识样本，我们期望识别新的生物标志物并为治疗靶向提供重要信息 tau 蛋白的致病形式。