Progression of Tau Pathology in AD

AD 中 Tau 蛋白病理学的进展

• 批准号: 6570773
• 负责人: Lester Irvin Binder
• 金额: $ 31.7万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-02-01 至 2007-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6570773
• 关键词: Alzheimer's disease; casein kinase; clinical research; confocal scanning microscopy; human tissue; immunocytochemistry; in situ hybridization; microarray technology; neurofibrillary tangles; neurons; northern blottings; pathologic process; phosphorylation; prosencephalon; protein isoforms; protein structure; tau proteins

DESCRIPTION (provided by applicant): The Neurofibrillary Tangles (NFTs) are found mainly in highly vulnerable long projection neurons in the Alzheimer's disease (AD) brain. The cholinergic neurons of the cholinergic basal forebrain (CBF) are exquisitely prone to NFT formation, and a progression of cellular changes is associated with tangle formation. However, the molecular events that underlie the formation of these lesions by the microtubule-associated tau protein remain unknown. Studies on the in vitro assembly of tau protomers into filaments strongly suggest that tau's transition from the soluble to the fibrillar form can be driven, in part, by phosphorylation and by C-terminal truncation accomplished in part by the action of caspases. Additionally, isoforms of the casein kinase 1 (CK1) phosphokinase family that deposit in granulovacuolar degeneration bodies (GVDs) are upregulated 10-30 fold in end stage AD. We propose to determine the order of appearance of these tau alterations in correlation with NFT formation in the cholinergic basal forebrain (CBF) long projection neurons. We hypothesize that the formation of the fibrillar pathologies is induced by a definable sequence of molecular events that directly impact tau "s assembly competency through phosphorylation and truncation. We will test this hypothesis by accomplishing the following specific aims: 1. Using antibodies against specific tau phosphopeptides, we propose to determine whether CBF neurons exhibit a progression of site-specific phosphorylation events that correlates with the transition from non-cognitive impairment (NCI), to mild cognitive impairment (MCI), early, and end-stage Alzheimer's disease (AD); 2. We propose to determine the progression of C-terminal tau truncation using well-characterized antibodies to D421 (the caspase site) and E 391 (another truncation site known to occur in AD); 3. Using antibodies to CKIalpha, CK1delta, and CKIepsilon, we will assay for the appearance of GVD bodies in CBF neurons during the progression from NCI-->MCI-->AD; and, 4. Using gene array technology, we propose to determine the relative quantities of CK1 message and the amounts of caspase message in individual CBF neurons from patients with the aforementioned clinical diagnoses.

描述（由申请人提供）：神经元缠结（NFT）主要存在于阿尔茨海默病（AD）大脑中高度脆弱的长投射神经元中。胆碱能基底前脑（CBF）的胆碱能神经元非常容易形成NFT，并且细胞变化的进展与缠结形成相关。然而，微管相关tau蛋白形成这些病变的分子基础仍然未知。对tau蛋白原聚体体外组装成细丝的研究强烈表明，tau蛋白从可溶性到纤维状形式的转变可以部分地通过磷酸化和部分地通过半胱天冬酶的作用完成的C-末端截短来驱动。此外，粒空泡变性体（GVD）中存款的酪蛋白激酶1（CK 1）磷酸激酶家族的亚型在终末期AD中上调10-30倍。 我们建议，以确定这些tau蛋白的改变与NFT形成的胆碱能基底前脑（CBF）长投射神经元的外观顺序。我们假设纤维状病变的形成是由一系列可定义的分子事件诱导的，这些分子事件通过磷酸化和截短直接影响tau蛋白的组装能力。我们将通过实现以下具体目标来检验这一假设：1。使用针对特定tau磷酸肽的抗体，我们提出确定CBF神经元是否表现出与从非认知障碍（NCI）到轻度认知障碍（MCI）、早期和终末期阿尔茨海默病（AD）的转变相关的位点特异性磷酸化事件的进展; 2.我们建议使用针对D421（半胱天冬酶位点）和E 391（已知在AD中发生的另一个截短位点）的充分表征的抗体来确定C末端tau截短的进展; 3.使用CK 1 α、CK 1 δ和CK 1 β的抗体，我们将检测从NCI->MCI->AD进展过程中CBF神经元中GVD小体的出现;以及，4.使用基因阵列技术，我们建议确定CK 1信息的相对数量和caspase信息的数量在个别CBF神经元从上述临床诊断的患者。