Altered APP metabolism triggers changes in tau that cause dementia

罕见的遗传性疾病通常揭示更常见的散发性形式的 同样的疾病，阿尔茨海默病(AD)也是如此。通常，阿尔茨海默病是一种老年人的疾病，然而， 中晚期常染色体显性遗传性AD(FAD)家族性形式的集合，但在其他方面非常 类似于散发性AD。所有FAD病例都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 一种以APP为底物的酶。APP位于21号染色体上，所有唐氏症患者 综合征(DS)在30-40岁时发展为AD神经病理，如果他们活得足够长，几乎所有的DS成年人 变得精神错乱。全部或部分21号染色体的三倍体是DS的主要原因，也会导致 提高APP的终身产量。这一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的几个蛋白分解片段被认为是致病的和 尽管目前还不确定哪些因素会引发AD级联，但人们普遍认为 微管相关蛋白tau在疾病的增殖过程中起关键作用。迅速增长的数据 提示tau可以以一种高度刻板的方式从一个神经元传播到另一个神经元，这与 阿尔茨海默病的症状出现。然而，对于细胞外tau或tau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，各种各样的tau物种被释放 来自原代啮齿动物皮质神经元和人类IPSC来源的皮质神经元(ICNs)。我们假设 野生型神经元释放的tau物种具有生理功能，而我们预计 此外，致病tau物种将从DS和FAD神经元中释放出来。因为时尚的载体和人 随着DS被预先确定为AD，我们将使用患者来源的DS和FAD iCN作为工具来识别 Tau的致病形式。这将涉及非痴呆患者的iCNs的培养液和裂解物的比较 对照，DS和FAD基因编辑的iCNs野生型APP二倍体表达细胞系和突变体 ICNs。这些分析将使用一系列新的免疫分析方法来研究tau的分子特性。 物种。使用DS、MCI、AD和非痴呆对照脑脊液样本的独特文库，我们将验证 疾病-在我们的iCNs中检测到的变化的相关性。之后，我们将测试是否预测到tau的致病形式 当细胞外应用时，诱导在DS和野生型iCNs的较老培养中看到的凋亡表型。 鉴于我们在IPSC技术方面的专业知识、复杂的tau检测系统以及对独特患者的访问 样本，我们希望识别新的生物标志物，并为治疗靶向提供重要信息。 Tau的致病形式。

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.