| First Author | Sundaram S | Year | 2019 |
| Journal | Sci Rep | Volume | 9 |
| Issue | 1 | Pages | 13743 |
| PubMed ID | 31551449 | Mgi Jnum | J:284881 |
| Mgi Id | MGI:6390018 | Doi | 10.1038/s41598-019-50197-x |
| Citation | Sundaram S, et al. (2019) Inhibition of casein kinase 1delta/epsilonimproves cognitive-affective behavior and reduces amyloid load in the APP-PS1 mouse model of Alzheimer's disease. Sci Rep 9(1):13743 |
| abstractText | 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 epsilon and delta, key circadian regulators, are significantly upregulated in AD and may contribute to AD pathogenesis. In the current studies, we have examined how inhibition of CK1epsilon/delta with PF-670462 (at 10 mg/kg, delta isoform selective, or 30 mg/kg, delta and epsilon selective) impacts regional Abeta 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 Abeta 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. |
