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Development of novel therapeutics to block Alzheimer's Disease progression

开发新疗法来阻止阿尔茨海默病的进展

基本信息

批准号：
10711989
负责人：
Gene D'Amour
金额：
$ 37.5万
依托单位：
XAVIER UNIVERSITY OF LOUISIANA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-24 至 2023-09-19
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10711989
关键词：
Affect African American population Alternative Splicing Alzheimer&apos s Disease Alzheimer&apos s disease pathology Alzheimer&apos s disease patient American Axon Binding Binding Proteins Biochemical Biological Assay Casein Kinase Iepsilon Cells Circadian Dysregulation Circadian Rhythms Collecting Cell Cytosol Databases Development Disease Disease Progression Dissociation Docking Fluorescence Resonance Energy Transfer Goals Hispanic Populations Homologous Gene In Vitro Incubated Individual Laboratory Finding Laboratory Research Lead Link Messenger RNA Microtubule Stabilization Microtubules Naphthoquinones Nature Neurofibrillary Tangles Neurons Not Hispanic or Latino Nuclear Pathologic Pathology Phosphorylation Phosphotransferases Probability Process Protein Isoforms Protein-Serine-Threonine Kinases Proteins Proteomics Quantitative Reverse Transcriptase PCR Reaction Recombinants Role Scheme Series Specificity Tau isoform ratio Tauopathies Testing Therapeutic Intervention Transcript Western Blotting blood-brain barrier permeabilization brain tissue casein kinase II course development design efficacy testing experimental study human old age (65+)improved in silico inhibitor neuroblastoma cell neurofibrillary tangle formation novel novel therapeutics overexpression prevent protein aggregation reconstitution tau Proteins tau-1 therapeutic candidate

项目摘要

Project Summary Alzheimer’s Disease (AD) afflicts over 6 million Americans, with African Americans being twice as likely as non- Hispanic whites to develop AD. Proteomic studies of AD patient brain tissue revealed increased expression of casein kinase 1 epsilon (CK1ε), a serine/threonine protein kinase. This overexpression of CK1ε has been shown to be correlated with multiple pathological features of AD, including the formation of neurofibrillary tangles (NFTs), alternation of tau protein isoform expression, and dysregulation of the circadian rhythm. NFTs are comprised of aggregates of an insoluble form of the microtubule binding protein tau. While tau normally binds to and stabilizes the microtubule array in neuronal axons, phosphorylation of tau leads to its dissociation and increases the probability of NFT formation. Previous studies show that CK1ε phosphorylates tau, causing tau to dissociate from microtubules and accumulate in the cytosol. As tau is an intrinsically disordered protein, its cytosolic accumulation increases its propensity to aggregate – the first step in the formation of NFTs. In addition to this direct role for CK1ε in the dissociation of tau from microtubules, there is an additional indirect role, in that CK1ε overexpression directly correlates with the increase of an alternatively spliced form of tau that reduces the number of microtubule binding repeats from four to three. The alteration of the ratio of tau isoforms is a hallmark of multiple tauopathies, including AD. Finally, increased CK1ε activity causes increased phosphorylation of period proteins (PER1/2) altering their core regulatory activity on the circadian rhythm. These findings suggest that CK1ε is a prime candidate for therapeutic intervention to slow the progressive nature of several pathologies associated with AD. Using computational docking studies, our research laboratory found a series of naphthoquinones to act as dual kinase CK1δ/ε inhibitors as well as those that are selective inhibitors of CK1ε. Structural features were identified on naphthoquinones that impart selectivity for CK1ε over its closest homolog, CK1δ (90% to 13% inhibition for 2-chloro-5,8-dihydroxynaphthoquinone and 96% to 1% for 2-bromo-5,8 dihydroxynaphthoquinone at 10μM concentration). One of the goals of the project is to optimize our lead compounds to increase their potency and specificity for CK1ε. We will use cellular and reconstituted biochemical assays to determine their efficacy in blocking the CK1ε-dependent phosphorylation of tau, the alternate splicing of the tau transcript, and the phosphorylation of period proteins.

项目总结