Development of novel therapeutics to block Alzheimer's Disease progression

Xavier University Of Louisiana, New Orleans LA

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Abstract

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.