Wheel-Running Behavior Is Negatively Impacted by Zinc Administration in a Novel Dual Transgenic Mouse Model of AD

Abstract

Alzheimer's disease (AD) is a neurocognitive disorder that impacts both the brain and behavior. Metal ions, including zinc (Zn), have been seen to play an important role in AD-related pathology. In this study, we show alterations in wheel-running behavior both early and late in disease progression in a novel dual Tg mouse model of AD. This mouse includes both amyloid and tau pathology through its cross with the J20 (hAPP) and P301L (Tau) parentage. Animals were given either lab water or water that had been supplemented with 10 ppm Zn. Wheel running was assessed through individually housing mice and measuring wheel-running activity in both the light and dark cycles. Dual Tg mice showed significantly less activity in the first part of the dark cycle than WT mice at both 3.5 and 7 months of age (p < 0.05). Dual Tg mice given Zn water showed less activity compared to dual Tg mice on lab water, tau mice on Zn water, or WT mice given either lab or Zn water (p < 0.05) at 7 months. Female mice in this study consistently showed higher activity compared to male mice in all groups whereas Zn led to reduced activity. Daily activity rhythm was altered in both the tau and dual Tg mice, and Zn impacted this alteration through effects on amyloid, tau, and through circadian pathways.

Keywords: Alzheimer’s disease; age; circadian activity; mouse model; sex; zinc.

FIGURE 1

Comparison of dark cycle activity by (A) Genotype by age and (B) age by genotype. Wildtype animals showed significantly higher total dark cycle activity than dual Tg animals at 7 months; hourly differences showed dual Tg animals were significantly less active than wildtypes early in the dark cycle, ZT12-17 at 3.5 months and ZT12-16 at 7 months. At 7 months tau animals were significantly less active than WT mice early in the dark cycle, ZT12-15, and significantly more active than WT mice later, ZT21-23 (^∗p < 0.05).

FIGURE 2

Comparison of dark cycle activity by (A) water type by age, (B) water type by genotype at 3.5 months, and (C) water type by genotype at 7 months. Tau animals exclusively showed a trend for increased activity from ZT 13-15 (^#) when administered Zn at 3.5 months. Dual Tg animals on Zn were significantly less active than all other groups except tau lab at 7 months (^∗p < 0.05, ^@p < 0.10, boxed ^# indicates a change summed across dark cycle hours).

FIGURE 3

Comparison of dark cycle activity by (A) sex by age, (B) sex by genotype at 3.5 months, and (C) sex by genotype at 7 months. Female animals showed significantly higher dark cycle activity compared to males at both 3.5 and 7 months (A). At 7 months, this increase was present in hours ZT 15-22 (all time intervals, p < 0.05). Female wild type animals were significantly more active than wild type males at both 3.5 and 7 months (^∗p < 0.05, boxed ^# indicates a significant effect summed across dark cycle hours).

FIGURE 4

Comparison dark cycle activity by (A) sex by water type by genotype at 3.5 months, and (B) sex by water type by genotype at 7 months. At 7 months, dual Tg females on lab water were significantly more active than either sex on Zn water, p < 0.05 (boxed ^# indicates a significant effect summed across dark cycle hours).