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.