Progression of Tau Pathology in AD

AD 中 Tau 蛋白病理学的进展

• 批准号: 7173789
• 负责人: Lester Irvin Binder
• 金额: $ 28.29万
• 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/7173789
• 关键词: Alzheimer' s Disease; Antibodies; Appearance; Attention; Basal Nucleus of Meynert; Binding; Biological Assay; Biological Models; Brain; C-terminal; CHK gene; Caspase; Choline Kinase; Cholinergic Agents; Complex; Cytokeratin-18 Staining Method; Data; Deposition; Disease; Episodic memory; Event; Exhibits; Family; Filament; Genes; Hippocampus (Brain); Human; Impaired cognition; In Vitro; Individual; Investigation; Laser Scanning Confocal Microscopy; Lesion; Measures; Microtubules; Molecular; Molecular Conformation; Neurofibrillary Tangles; Neurons; Numbers; Pathologic; Pathology; Patients; Phosphopeptides; Phosphorylation; Phosphorylation Site; Population; Process; Protein Isoforms; Relative (related person); Research Personnel; Site; Staging; Staining method; Stains; Technology; Testing; Tissue Harvesting; Transcript; basal forebrain; basal forebrain cholinergic neurons; brain tissue; casein kinase I; cholinergic; cholinergic neuron; clinical Diagnosis; mild neurocognitive impairment; nerve supply; neurofibrillary tangle formation; programs; tau Proteins; tau aggregation

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.

神经原纤维缠结（nft）主要发现于高度脆弱的长投射