Effects of aging and genotype on circadian rhythms, sleep, and clock gene expression in APPxPS1 knock-in mice, a model for Alzheimer's disease

Abstract

Profound disruptions of circadian rhythms and sleep/wake cycles constitute a major cause of institutionalization of AD patients. This study investigated whether a rodent model of AD, APP(NLH/NLH)/PS-1(P264L/264L) (APPxPS1) mice, exhibits circadian alterations. The APPxPS1 mice were generated using CD-1/129 mice and Cre-lox knock-in technology to "humanize" the mouse amyloid (A)β sequence and create a presenilin-1 mutation identified in familial early-onset AD patients. APPxPS1 and WT mice of several ages (~4, 11, and 15 months) were monitored for circadian rhythms in wheel running, cage activity, and sleep:wake behavior. After rhythm assessment, the mice were euthanized at zeitgeber time (ZT) 2 or 10 (i.e., 2 or 10 h after lights-on) and brains were dissected. Amyloidβ levels were measured in cortical samples and brain sections of the hypothalamus and hippocampus were prepared and used for in situ hybridization of circadian or neuropeptide genes. The most significant effects of the APPxPS1 transgenes were phase delays of ~2 h in the onset of daytime wakefulness bouts (P<0.005) and peak wakefulness (P<0.02), potentially relevant to phase delays previously reported in AD patients. However, genotype did not affect the major activity peaks or phases of wheel running, wake, or general movement, which were bimodal with dominant dawn and dusk activity. Expression of Period 2 in the suprachiasmatic nucleus was affected by ZT (P<0.0001) with a marginal interaction effect of age, genotype, and ZT (P<0.08). A separate analysis of the old animals indicated a robust interaction between ZT and genotype, as well as main effects of these parameters. Aging also altered sleep (e.g., bout length and amount of daytime sleep) and the amount of wheel running and cage activity. In conclusion, the APPxPS1 knock-in mice exhibit some alterations in their sleep:wake rhythm and clock gene expression, but do not show robust, genotype-related changes in activity rhythms. The prominent daytime activity peaks shown by the background strain complicate the use of these APPxPS1 knock-in mice for investigations of circadian activity rhythms in AD. In addition to this unusual activity pattern, lack of hyperactivity differentiates the APPxPS1 knock-in mice from other transgenic AD models.