Human ApoE ε4 alters circadian rhythm activity, IL-1β, and GFAP in CRND8 mice.

Abstract

Disruptions to daily living, inflammation, and astrogliosis are characteristics of Alzheimer's disease. Thus, circadian rhythms, nest construction, IL-1β and TNF-α, and glial fibrillary acidic protein (GFAP) were examined in a mouse model developed to model late-onset Alzheimer's disease-the most common form of the disease. Mice carrying both the mutated human AβPP transgene found in the CRND8 mouse and the human apolipoprotein E ε4 allele (CRND8/E4) were compared with CRND8 mice and wildtype (WT) mice. Circadian rhythms were evaluated by wheel-running behavior. Activity of daily living was measured by nest construction. This study then examined mRNA levels of the inflammatory cytokines IL-1β and TNF-α as well as protein levels of GFAP. Behavioral outcomes were then correlated with cytokines and GFAP. Compared to WT controls, both CRND8 and CRND8/E4 mice showed significantly more frequent, but shorter, bouts of activity. In the three groups, the CRND8/E4 mice had intermediate disruptions in circadian rhythms. Both CRND8/E4 mice and CRND8 mice showed significant impairments in nesting behavior compared to WTs. While CRND8 mice expressed significantly increased IL-1β and GFAP expression compared to WT controls, CRND8/E4 mice expressed intermediate IL-1β and GFAP levels. Significant correlations between IL-1β, GFAP, and behavior were observed. These data are congruent with other studies showing that human ApoE ε4 is protective early in life in transgenic mice modeling Alzheimer's disease.