A Longitudinal Investigation into the Effects of Zn and Cu on Spatial Learning/Memory and Social Preference in a Mouse Model of LOAD

Stefanie N. Howell

Advisor: Jane M Flinn, PhD, Department of Psychology

Committee Members: Jennifer Brielmaier, Craig McDonald

David J. King Hall, #2027
December 06, 2016, 10:00 AM to 07:00 AM


This study examined the effects of dietary copper (Cu) and zinc (Zn) on spatial learning/memory and social preference in a mouse model of late onset Alzheimer’s disease (AD).  Previous research has indicated that excess dietary Zn may cause behavioral impairments through an induced Cu deficiency. Using a mildly Cu deficient hard diet, we initially tested this theory in an early onset model of AD, which suggested instead that 1.) the effects of Cu and Zn may differ in the brain regions controlling different behaviors, and that 2.) the effect of excess Zn may not be entirely due to an induced Cu deficiency.

To examine the effects of the dietary manipulations in a late onset model, we crossed male hAPP transgenic (Tg) mice with homozygous ApoE4 females.  We were particularly interested in the E4 allele of the APOE gene, as it constitutes a high risk factor for development of AD, with some evidence showing that it may be protective early on.  Six groups were tested for spatial learning/memory (Morris water maze (MWM)) and social preference (3-chamber apparatus) at 6 and 12 months of age (wildtype (Wt) and Tg mice on (a.) lab water + Cu control diet, (b.) lab water + Cu deficient diet, or (c.) Zn-enhanced water + Cu control diet). These time points were chosen to identify longitudinal changes in behavior, allowing for identification of the potentially protective effects of the E4 allele and dietary interactions in early and late stages of AD.  Open field (OF) and olfactory habituation/dishabituation (OHD) were assessed as controls for the social behavior task (locomotor activity and odor sensitivity respectively).

 Data at 6 months suggests early spatial learning/memory deficits but intact social preference in AD mice. AD mice showed significantly longer latencies, fewer platform crossings, and spent less time in the target quadrant than Wt’s in the MWM (p<.001), but display normal preferences for social interaction in the 3-chamber test. Tg Cu deficient and Zn mice display a normal preference for social novelty/recognition memory, indicating that excess Zn, whether direct or indirect, may uniquely improve behavior on this task. At 12 months, there remains a significant difference between genotypes in measures of MWM, but no significant differences were seen in the social behavior task.