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.
Despite the prevalence and well-recognized adverse effects of prenatal alcohol exposure and alcohol use disorder in the causation of numerous diseases, their potential roles in the etiology of neurodegenerative diseases remain poorly characterized. This is especially true of the rare neurodegenerative diseases, for which small population sizes make it difficult to conduct broad studies of specific etiological factors. Nonetheless, alcohol has potent and long-lasting effects on neurodegenerative substrates, at both the cellular and systems levels. This review highlights the general effects of alcohol in the brain that contribute to neurodegeneration across diseases, and then focuses on specific diseases in which alcohol exposure is likely to play a major role. These specific diseases include dementias (alcohol-induced, frontotemporal, and Korsakoff syndrome), ataxias (cerebellar and frontal), and Niemann-Pick disease (primarily a Type B variant and Type C). We conclude that there is ample evidence to support a role of alcohol abuse in the etiology of these diseases, but more work is needed to identify the primary mechanisms of alcohol’s effects.
Time-of-day effects have been noted in a wide variety of cognitive behavioral tests, and perturbation of the circadian system, either at the level of the master clock in the SCN or downstream, impairs hippocampus-dependent learning and memory. A number of kinases, including the serine-threonine casein kinase 1 (CK1) isoforms CK1δ/ε, regulate the timing of the circadian period through post-translational modification of clock proteins. Modulation of these circadian kinases presents a novel treatment direction for cognitive deficits through circadian modulation. Here, we tested the potential for PF-670462, a small molecule inhibitor of CK1δ/ε, to improve cognitive performance in C57BL/6J mice in an array of behavioral tests. Compared to vehicle-treated mice tested at the same time of the circadian day, mice treated with PF-670462 displayed better recall of contextual fear conditioning, made fewer working memory errors in the radial arm water maze, and trained more efficiently in the Morris Water Maze. These benefits were accompanied by increased expression of activity-regulated cytoskeleton-associated protein (Arc) in the amygdala in response to an acute learning paradigm. Our results suggest the potential utility of CK1δ/ε inhibition in improving time-of-day cognitive performance.
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