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bioRxiv · 10.1101/539627

Therapeutic Targeting of Casein Kinase 1δ/ε in an Alzheimer's Disease Mouse Model

Adler, P.·Mayne, J.·Walker, K.·Ning, Z.·Figeys, D.
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Abstract

Sleep disturbances and memory impairment are common symptoms of Alzheimers disease (AD). Given that the circadian clock regulates sleep, hippocampal function, and neurodegeneration, it represents a therapeutic target against AD. Casein kinase 1{delta}/{varepsilon} (CK1{delta}/{varepsilon}) are clock regulators and overexpressed in AD brains, making them viable targets to improve sleep and cognition. We assessed the effects of a small molecule CK1{delta}/{varepsilon} inhibitor (PF-670462) in a cellular model of circadian clocks and in 3xTg-AD mice. Mass spectrometry-based proteomic analyses revealed that PF-670462 treatment in vitro upregulated multiple proteins that are downregulated in AD, while administration in 3xTg-AD mice reversed hippocampal proteomic alterations in diverse AD-associated and clock-regulated pathways, including synaptic plasticity and amyloid precursor protein processing. Furthermore, PF-670462 rescued working memory and normalized behavioural circadian rhythms in 3xTg-AD mice. Our study provides proof of concept for CK1{delta}/{varepsilon} inhibition and direct clock modulation against AD-related proteomic changes, memory impairment, and circadian disturbances.

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Adler, P., Mayne, J., Walker, K., Ning, Z., Figeys, D.. 2019-02-03. Therapeutic Targeting of Casein Kinase 1δ/ε in an Alzheimer's Disease Mouse Model. https://doi.org/10.1101/539627

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