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

Sleep disturbances and memory impairment are common symptoms of Alzheimer's disease (AD). Given that the circadian clock regulates sleep, hippocampal function, and neurodegeneration, it represents a therapeutic target against AD. Casein kinase 1δ/ε (CK1δ/ε) are clock regulators and overexpressed in AD brains, making them viable targets to improve sleep and cognition. In this study, we evaluated the therapeutic potential of a small molecule CK1δ/ε inhibitor (PF-670462) in a triple transgenic mouse model of AD (3xTg-AD). Mass spectrometry-based proteomic analyses revealed that PF-670462 administration in 3xTg-AD mice reversed hippocampal proteomic alterations in several AD-related and clock-regulated pathways, including synaptic plasticity and amyloid precursor protein processing. Furthermore, PF-670462 administration rescued working memory deficits and normalized behavioral circadian rhythm disturbances in 3xTg-AD mice. Our study provides in vivo proof of concept for CK1δ/ε inhibition against AD-associated hippocampal proteomic changes, memory impairment, and circadian disturbances.