Effects of enhanced dietary consumption of zinc and iron on phenotype and Alzheimer-like pathology in Tg2576 mice

This experiment examined metals and the pathogenesis of Alzheimer disease (AD). Elevated levels of zinc, iron, and copper have been reported in beta-amyloid (Abeta) plaques and adjacent tissue in AD brains (e.g. Flinn et al., 2003) and there is significantly more exchangeable Zn 2+ in the cerebrovasculature of transgenic models of AD (Friedlich et al., 2004). In this study, wild type (Wt) and transgenic (Tg) 2576 mice (Hsiao et al., 1996) were administered (ad libidum in drinking water) soluble zinc (10 ppm ZnCO3) or iron (5 ppm Fe(NO3) 2).; Behaviour, brain levels of metal, and plaque morphology (for Tg2576 mice) were characterized. A Morris water maze (Atlantis and moving platform paradigms) were used for behavioural testing. Microprobe synchrotron X-ray fluorescence (muSXRF) was used to quantify total brain metal (K, Fe, Cu, and Zn) in the dorsal hippocampus. Amyloid deposits were examined with Congo red and Thioflavin-S. Chelatable iron deposits were assessed with Prussian blue. Qualitative measurements of vesicular zinc intensity were imaged using ZPI histofluorescence. Additionally, muSXRF was used to quantify metal levels in human (AD and non-AD control) tissue.; In assessments of murine behaviour, spatial memory deficits and changes in brain metal localization were associated with ZnCO3 or Fe(NO 3)2 consumption in Wt2576 and Tg2576 mice. The most profound behavioural deficits were associated with ZnCO3 treatment in both genotypes. Tg2576 ZnCO3 mice (particularly males) were significantly more impaired than any other group, and, moreover, Wt2576 ZnCO3 animals often performed worse than Tg2576 mice receiving lab water. In some measures, Tg2576 mice were more vulnerable to zinc-related behavioural changes than Wt2576 mice. This suggests behavioural impairments were more than just the summation of soluble zinc bioavailability and potentially dangerous Abeta. Changes of metal levels in the brain were associated with ZnCO3 treatment, specifically greater zinc intensity levels in the Mol+ region (molecular layer and adjacent tissue) of the dorsal hippocampus in Tg2576 mice.; Overall, Abeta-rich Tg2576 mouse tissue and AD human tissue harboured more zinc, copper, potassium, and particularly more iron than controls (non-AD tissue). While metal levels were highest in plaque areas, some comparisons revealed that metal translocation in the brain is a dynamic process during neurodegeneration. In areas of non-AD brain tissue where greater amounts of metal was found relative to AD tissue, it was most likely because that in diseased tissue these metal populations may have already been sequestered by plaques, meninges, or mediated by some other unknown process.; In assessments of Tg2576 mice, plaque burden was least in Tg2576 mice consuming ZnCO3 and plaque burden showed patterns of being elevated in Fe(NO3)2 Tg2576 mice, relative to lab water (control) Tg2576 mice. Surprisingly, animals with the most profound impairments were ZnCO3-treated mice with the least plaque accumulation.; In some cases there was a tendency for Fe(NO3)2-treated Tg2576 mice with larger plaques (but little diffuse amyloid) to be less impaired than expected and, like lab water Tg2576 mice, were less impaired than ZnCO3 animals. Zinc-treated Tg2576 behaviour was novel, as deficits were related to fewer plaques, in contrast to the other Tg2576 groups, where greater behavioural impairments were associated with more plaques.