Human ApoE ε4 Alters Circadian Rhythm Activity, IL-1β, and GFAP in CRND8 Mice

Article type: Research Article

Authors: Graybeal, John J.^{a; 1} | Bozzelli, P. Lorenzo^{a; 1} | Graybeal, Lacey L.^b | Groeber, Caitlin M.^a | McKnight, Patrick E.^a | Cox, Daniel N.^c | Flinn, Jane M.^{a; *}

Affiliations: [a] Department of Psychology, George Mason University, Fairfax, VA, USA | [b] Department of Molecular Neuroscience, Krasnow Institute for Advanced Study, George Mason University, Fairfax, VA, USA | [c] School of Systems Biology, Krasnow Institute for Advanced Study, George Mason University, Fairfax, VA, USA

Correspondence: [*] Correspondence to: Jane M. Flinn, Director, Undergraduate Program in Neuroscience, George Mason University, MSN 3F5, 4400 University Drive, Fairfax, VA 22030, USA. Tel.: +1 703 993 4107; Fax: +1 703 993 1359; E-mail: jflinn@gmu.edu.

Note: [1] These authors contributed equally to this work.

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.

Keywords: Alzheimer's disease, apolipoprotein E4, circadian rhythm, cytokines, glial fibrillary acidic protein, gliosis, IL-1β, nesting behavior, TNF-α, transgenic mice

DOI: 10.3233/JAD-132009

Journal: Journal of Alzheimer's Disease, vol. 43, no. 3, pp. 823-834, 2015