ABSTRACT
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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 Aß 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 Aß 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.
ABSTRACT
OBJECTIVE: To determine patterns of fecal shedding of feline coronavirus (FCV) by cats, age at which kittens first began to shed FCV in their feces, and whether there was any relationship between fecal shedding of FCV and serum antibody titers in adult cats or kittens. DESIGN: Prospective observational study. ANIMALS: 15 adult cats and 18 kittens from a single cattery. PROCEDURE: Blood and fecal samples were collected from adult cats every other month for 13 months. Serum FCV antibody titers were measured by use of an indirect immunofluorescence assay. A reverse-transcriptase, nested polymerase chain reaction assay was used to detect FCV in feces. Blood and fecal samples were collected from kittens at approximately 2-week intervals from 3 weeks to 15 weeks of age. RESULTS: Adult cats shed FCV intermittently. All adult cats shed virus in their feces at least once during the year, and 4 of 15 shed virus > 75% of the time. Serum antibody titer was not significantly associated with shedding of FCV. For the kittens, median age at the time FCV was first detected in feces was 67 days (range, 33 to 78 days). All except 1 of the kittens was found to be shedding virus in their feces before or at the time of seroconversion. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that serum FCV antibody titers are not a good indicator of shedding of FCV in the feces. Kittens may shed FCV in their feces before they seroconvert, and all kittens in a cattery in which FCV infection is endemic may be infected before 12 weeks of age.
