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

Abstract

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. We assessed the effects of a small molecule CK1δ/ε 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 CK1δ/ε inhibition and direct clock modulation against AD-related proteomic changes, memory impairment, and circadian disturbances.

Evaluating Circadian Dysfunction in Mouse Models of Alzheimer’s Disease: Where Do We Stand?

“…Moreover, Sterniczuk et al (2010) show increased amplitude and daytime activity in four month old male mice while female mice show a decreased amplitude by 11 months. Finally, Adler et al (2019) showed a shortened period and decreased amplitude in 3xTG mice which was ameliorated by inhibiting casein kinase 1δ and 1ε, enzymes that are important for the degradation of PER proteins and maintenance of core clock function. Thus, while the 3xTG mouse shows some promise as a more accurate model of AD-like circadian changes, the inconsistency across studies makes interpretation difficult.…”

Role of Kalirin and mouse strain in retention of spatial memory training in an Alzheimer’s disease model mouse line

“…While some researchers have reported that 3xTG-H mice move more slowly than B6129 mice in the open field (Fertan et al, 2019;Nakajima et al, 2015;Torres-Lista et al, 2019), others have reported no differences in open field testing (Adler et al, 2019;Li et al, 2018;Lin et al, 2019;Nie et al, 2017;Sterniczuk et al, 2010a;Yu et al, 2015) or increased mobility in 3xTG-H mice (Krivinko et al, 2017;Stover et al, 2015). As in most similar studies, there were no sex differences in these open field and rotarod results (Gawel et al, 2019).…”

Changes in 24 h Rhythmicity of Spontaneous Locomotor Activity in the Triple Transgenic Mouse for Alzheimer’s Disease (3xTg-AD) in a Jet Lag Protocol: Correlations with Retinal Sensitivity

“…Stopa et al [ 45 ] found neurofibrillary tangles in the SCN of patients with advanced dementia. It has been noted in other studies that AD is associated with changes in the activity of phosphorylating enzymes, such as casein kinase I [ 46 ], and that modulation of the activity of casein kinase I δ/ɛ changes the free-running period and advances or delays in entrainment to LD [ 47 ]. Therefore, phosphorylation of molecular components of the circadian clock is linked to the implementation of a short free-running period and advanced onset of activity.…”