Progression of Tau Pathology in AD

神经原纤维缠结(NFT)主要见于高度易损的长投射。 阿尔茨海默病(AD)大脑中的神经元。胆碱能基础上的胆碱能神经元 前脑(CBF)非常容易形成NFT，细胞变化的进展是 与纠缠形成有关。然而，这些形成的分子事件 微管相关tau蛋白引起的损伤仍不清楚。微球的体外组装研究 形成细丝的tau原形分子强烈地表明tau从可溶形式转变为纤维形式 部分由磷酸化驱动，部分由C-末端截断驱动，部分由 半胱氨酸酶的作用。此外，酪蛋白激酶1(CK1)磷酸激酶家族的异构体 在终末期AD中，颗粒泡变性小体(GVD)的沉积增加了10-30倍。 我们建议确定这些tau改变的出现顺序与NFT的相关性 胆碱能基底前脑(CBF)长投射神经元的形成。我们假设 纤维病变的形成是由一系列可定义的分子事件引起的，这些分子事件直接 通过磷酸化和截断来影响S的组装能力。我们将检验这一假设 通过实现以下特定目的：1.使用针对特定tau磷酸肽的抗体， 我们建议确定CBF神经元是否表现出部位特异性磷酸化的进展。 与从非认知障碍(NCI)向轻度认知障碍转变相关的事件 损害(MCI)、早期和终末期阿尔茨海默病(AD)；2.我们建议确定 利用抗D-421(半胱氨酸天冬氨酸氨基转移酶)特异性抗体截断Tau C-末端的研究进展 和E 391(已知在AD中发生的另一个截断位点)；3.使用针对CKI_1、CK18和 CKI_，我们将检测CbF神经元中GVD小体的出现。 NCI--&GT；MCI--&GT；AD；以及，4.利用基因芯片技术，我们提出了确定相对量 CK1信使和Caspase信使在单个CBF神经元中的量 前述临床诊断。

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 D 421 (the caspase site) and E 391 (another truncation site known to occur in AD); 3. Using antibodies to CKI_, CK18, and CKI_, 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.