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:
  • 金额:
    $ 22.19万
  • 依托单位:
  • 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

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.
罕见的遗传性疾病往往揭示了更常见的散发性疾病的重要信息。 同样的疾病,这对阿尔茨海默病(AD)来说也是如此。通常,AD是老年人的疾病,然而, 一组常染色体显性遗传的家族性AD(fAD)在中年晚期发作,但在其他方面非常 类似于散发性AD。所有fAD病例均归因于三种基因之一的突变:APP、PSEN 1或 PSEN2. APP编码淀粉样前体蛋白(APP),PSEN基因编码淀粉样前体蛋白的活性位点。 以APP为底物的酶。APP位于21号染色体上, 综合征(DS)患者在30- 40岁时发展成AD神经病理学,如果他们活得足够长,几乎所有DS成人 变得精神错乱21号染色体的全部或部分三倍化是DS的主要原因,也导致 这一有说服力的遗传学证据表明,APP起着核心作用, 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的, 虽然不确定是哪一种引发了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。新兴数据 这表明tau蛋白可以以一种高度刻板方式在神经元之间传播, 出现AD症状。然而,关于细胞外tau蛋白的分子特性或细胞外tau蛋白的分子特性知之甚少。 它从细胞中释放出来的过程。我们最近发现各种tau蛋白被释放出来, 来自原代啮齿动物皮层神经元和人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种类将从DS和fAD神经元释放。由于FAD载体和人员 由于DS预先确定会发展为AD,我们将使用患者源性DS和fAD iCN作为工具, Tau的致病形式。这将涉及比较来自非痴呆症患者的iCN的培养基和裂解物。 对照、来自DS和fAD基因编辑的野生型APP二倍体表达细胞系和突变体的iCN iCN。这些分析将采用一系列新的免疫测定来研究tau蛋白的分子特性 物种使用DS、MCI、AD和非痴呆对照CSF样本的独特文库,我们将验证 在iCN中检测到的变化的疾病相关性。此后,我们将测试预测的致病形式的tau蛋白 当细胞外应用时,诱导在DS和野生型iCN的旧培养物中观察到的凋亡表型。 鉴于我们在iPSC技术,复杂的tau检测系统,以及获得独特的患者 样本,我们希望确定新的生物标志物,并提供重要的信息,为治疗靶向 Tau的致病形式。

项目成果

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Tracy L YOUNG-PEARSE其他文献

Tracy L YOUNG-PEARSE的其他文献

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{{ truncateString('Tracy L YOUNG-PEARSE', 18)}}的其他基金

Cell and Molecular Consequences of Alzheimer's Disease Genetic Variants on BBB Integrity and Function
阿尔茨海默病遗传变异对血脑屏障完整性和功能的细胞和分子影响
  • 批准号:
    10037760
  • 财政年份:
    2020
  • 资助金额:
    $ 22.19万
  • 项目类别:
Establishing a human cellular model of sex differences in the brain
建立大脑性别差异的人类细胞模型
  • 批准号:
    9752715
  • 财政年份:
    2019
  • 资助金额:
    $ 22.19万
  • 项目类别:
Establishing a human cellular model of sex differences in the brain
建立大脑性别差异的人类细胞模型
  • 批准号:
    9904767
  • 财政年份:
    2019
  • 资助金额:
    $ 22.19万
  • 项目类别:
Probing Heterogeneity of Alzheimer's disease using iPSCs
使用 iPSC 探索阿尔茨海默病的异质性
  • 批准号:
    10159823
  • 财政年份:
    2018
  • 资助金额:
    $ 22.19万
  • 项目类别:
Probing Heterogeneity of Alzheimer's disease using iPSCs
使用 iPSC 探索阿尔茨海默病的异质性
  • 批准号:
    10400951
  • 财政年份:
    2018
  • 资助金额:
    $ 22.19万
  • 项目类别:
Probing Heterogeneity of Alzheimer's disease using iPSCs
使用 iPSC 探索阿尔茨海默病的异质性
  • 批准号:
    9923549
  • 财政年份:
    2018
  • 资助金额:
    $ 22.19万
  • 项目类别:
Probing Heterogeneity of Alzheimer's Disease Using iPSCs
使用 iPSC 探索阿尔茨海默病的异质性
  • 批准号:
    10657140
  • 财政年份:
    2018
  • 资助金额:
    $ 22.19万
  • 项目类别:
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
  • 财政年份:
    2016
  • 资助金额:
    $ 22.19万
  • 项目类别:
Detection of cell type specific effects of pathway manipulation in neural cells
检测神经细胞中通路操纵的细胞类型特异性效应
  • 批准号:
    8831313
  • 财政年份:
    2014
  • 资助金额:
    $ 22.19万
  • 项目类别:
Genes and developmental signaling pathways in neuropsychiatric disorders
神经精神疾病的基因和发育信号通路
  • 批准号:
    9229296
  • 财政年份:
    2014
  • 资助金额:
    $ 22.19万
  • 项目类别:

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