An Investigation into the Role of Copper Deficiency and Zinc in a Mouse Model of Early Onset Alzheimer’s Disease

Abstract

While significant advances have been made in understanding the neural mechanisms of Alzheimer’s disease (AD), many aspects remain unknown. More recent theories revolve around the effects of metals in the diseased brain. Building on research previously conducted in our lab, this study examined the roles of two metals, zinc (Zn) and copper (Cu), in a mouse model of early onset AD. The previously mentioned studies found that excess Zn caused behavioral impairments in rats and mice; however, the addition of Cu to the Zn-enhanced water remediated the negative effects seen in the purely Zn group. This supports the theory that the effects of “excess Zn” were due to an induced Cu deficiency. To test this theory it was necessary to look at a Cu deficiency directly. For this purpose, we, together with Harlan laboratory nutritionists, developed a specialized Cu deficient and Cu control diet (differing only in levels of Cu). Wildtype (Wt) (C57Bl/6J) and transgenic (Tg) mice with one copy of a doubly mutated human amyloid precursor protein (hAPP) gene (J20; breeders obtained from the Jackson Laboratory) were raised in one of three groups: a strictly control group (lab water + control diet), or one of two experimental conditions involving excess Zn (Znwater + control diet) and a diet deficient in Cu (Cu deficient diet + lab water). Mice were run in two behavioral tasks, novel object recognition (NOR) and Morris water maze (MWM), aimed at identifying the effects of the metals on memory deficits seen early in AD patients. Mice were tested beginning at 6 months of age. All Wt and Tg groups distinguished the novel object at 15-minutes, groups varied widely at 1 hour, and no differences were seen at 24-hours. In MWM, there was a significant difference between Wt and Tg mice on all measures. Cu-deficient Tg mice were trending toward a significant difference in latency on day 3 from the Zn-enhanced group, who were slower to learn the task. Within the Tg group (MWM), Cu deficient mice unexpectedly performed the best overall, the controls performed intermediately and the Zn-enhanced group showed the worst performance. The differing patterns seen in MWM and NOR indicate that the effects of Cu and Zn are dependent upon different brain structures, and that the Zn effect is not entirely due to an induced Cu deficiency.