Abstract
Circadian rhythm disruption is one of the earliest biomarkers of Alzheimer’s disease (AD), and there exists a bidirectional relationship by which dysfunctions in the circadian clock drive AD pathology and AD pathology drives circadian dysfunction. Casein kinase 1 (CK1) isoforms ε and δ, key circadian regulators, are significantly upregulated in AD and may contribute to AD pathogenesis. In the current studies, we have examined how inhibition of CK1ε/δ with PF-670462 (at 10 mg/kg, δ isoform selective, or 30 mg/kg, δ and ε selective) impacts regional Aβ and circadian gene expression in 10–13 month old APP-PS1 mice and nontransgenic controls. We have also assessed circadian, cognitive, and affective behavioral correlates of these neural changes. At baseline, APP-PS1 mice showed a short period, as well as impaired cognitive performance in both prefrontal cortex and hippocampus-dependent tasks. Both doses of PF-670462 lengthened the period and improved affect, whereas only the higher dose improved cognition. Further, PF-670462 treatment produced a dose-dependent reduction in amyloid burden – overall Aβ signal decreased in all three areas; in the prefrontal cortex and hippocampus, PF-670462 also reduced plaque size. Together, these findings support chronotherapy as a potential tool to improve behavior in AD.
Highlights
Circadian rhythm disruption is one of the earliest biomarkers of Alzheimer’s disease (AD), and there exists a bidirectional relationship by which dysfunctions in the circadian clock drive AD pathology and AD pathology drives circadian dysfunction
We first assessed the baseline rhythmicity in amyloid precursor protein (APP)-PS1 mice vs. nontransgenic controls in 12:12 light dark cycles (LD) and in constant darkness (DD)
We found no difference between genotypes in 12:12LD, but found a significantly shorter period in APP-PS1 mice (23.69 vs. 23.95; F(1,49) = 5.21, p < 0.01) in DD (Fig. 1A,B)
Summary
Circadian rhythm disruption is one of the earliest biomarkers of Alzheimer’s disease (AD), and there exists a bidirectional relationship by which dysfunctions in the circadian clock drive AD pathology and AD pathology drives circadian dysfunction. APP-PS1 mice showed a short period, as well as impaired cognitive performance in both prefrontal cortex and hippocampus-dependent tasks. PF-670462 treatment produced a dose-dependent reduction in amyloid burden – overall Aβ signal decreased in all three areas; in the prefrontal cortex and hippocampus, PF-670462 reduced plaque size Together, these findings support chronotherapy as a potential tool to improve behavior in AD. More salient to early interventions in AD, recent studies have demonstrated that circadian rhythm disorders occur years before clinical symptoms, and loss of rhythmicity contributes to the early accumulation of β-amyloid peptide and later cognitive deficits, as www.nature.com/scientificreports/. The circadian clock is an endogenous timekeeping system designed to control the timing of numerous molecular and physiological processes This system is highly conserved, allowing organisms from fungi to mammals to anticipate and adapt to daily changes in the environment. This may be one reason that individuals with AD are phase delayed10 - they typically go to sleep later than the rest of the population
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