Rational development of a small-molecule activator of CK1γ2 that decreases C99 and beta-amyloid levels

Abstract

Alzheimers disease (AD) is a debilitating neurodegenerative disorder characterized by the accumulation of beta-amyloid (A{beta}), C99, and Tau in vulnerable areas of the brain. Despite extensive research, current strategies to lower A{beta} levels have shown limited efficacy in slowing the cognitive decline associated with AD. Recent findings suggest that C99 may also play a crucial role in the pathogenesis of AD. Our laboratory has discovered that CK1{gamma}2 phosphorylates Presenilin 1 at the {gamma}-secretase complex, leading to decreased C99 and A{beta} levels. Thus, CK1{gamma}2 activation appears as a promising therapeutic target to lower both C99 and A{beta} levels. In this study, we demonstrate that CK1{gamma}2 is inhibited by intramolecular autophosphorylation and describe a high-throughput screen designed to identify inhibitors of CK1{gamma}2 autophosphorylation. We hypothesize that these inhibitors could lead to CK1{gamma}2 activation and increased PS1-Ser367 phosphorylation, ultimately reducing C99 and A{beta} levels. Using cultured cells, we investigated the impact of these compounds on C99 and A{beta} concentrations and confirmed that CK1{gamma}2 activation effectively reduces their levels. Our results provide proof of concept that CK1{gamma}2 is an attractive therapeutic target for AD. Future studies should focus on the identification of specific compounds that can inhibit CK1{gamma}2 autophosphorylation and evaluate their efficacy in preclinical models of AD. These studies will pave the way for the development of novel therapeutics for the treatment of AD.