Progression of Tau Pathology in AD

描述（由申请人提供）：神经原纤维缠结（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的形成有关。然而，微管相关tau蛋白形成这些病变的分子事件仍然未知。对tau原蛋白在体外组装成细丝的研究强烈表明，tau从可溶性到纤维状的转变可以部分由磷酸化和部分由半胱天冬酶作用完成的c端截断驱动。此外，沉积在颗粒空泡变性体（GVDs）中的酪蛋白激酶1 （CK1）磷酸激酶家族的同工型在终末期AD中上调10-30倍。

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.