Characterization of a Novel hAPP/Tau Mouse Model of Alzheimer's Disease: Exploring the Impact of Zinc Supplementation

Stephen L. P. Lippi

Major Professor: Jane M Flinn, PhD, Department of Psychology

Committee Members: Tyler Shaw, Geraldine Grant

David King Hall, #2046
April 09, 2018, 10:30 AM to 12:30 PM

Abstract:

Mice bearing both amyloid and tau pathology are critical for modelling and studying Alzheimer’s disease (AD). Through use of these double transgenic mice, researchers can study how both interact and lead to disturbances in the brain and behavior. In this study, we characterize offspring from the cross of the J20 (hAPP) and rTg4510 (tau) mouse strains, behaviorally at both three and a half and seven months and biochemically at eight months, on and off zinc (Zn) water. The double Tg mice (hAPP/Tau) were compared to single tau mice containing the P301L tau mutation under the CaMKIIa promoter, mice solely expressing the promoter with no tau mutation, and wildtype (WT) mice with no mutations. hAPP/Tau mice spent less time in the center of the open field, indicative of increased anxiety and made more head dips and spent more time in the open arms of the elevated zero maze (EZM) compared to WT mice (p < .001), in contrast displaying anxiolytic behavior. hAPP/Tau mice showed deficits in spatial memory as assessed by the Barnes Maze; hAPP/Tau mice spent significantly less time in the target quadrant during the seventh day probe trial compared to WT mice and worsened with age (p < .01). hAPP/Tau mice spent longer amounts of time swimming at seven months compared to three and a half months in the forced swim (FS) test (p < .05). In the brain, hAPP/Tau mice had significantly less free zinc compared to WT mice in both the dentate gyrus and the CA3 of the hippocampus (p < .001) as detected by Zinpyr-1 fluorescence. hAPP/Tau mice and single tau mice had significantly greater inflammation, seen through GFAP immunoblotting, than CaMKIIa promoter mice (p < .05). Plaques and increased Thioflavin-S fluorescence were noted in the hippocampus of hAPP/Tau mice compared to single tau mice. Animals given Zn water displayed increased tangle pathology, as seen by greater Thioflavin-S fluorescence in the hippocampus. hAPP/Tau mice showed severe behavioral deficits at the first testing period which may have masked any effects Zn supplementation may have been playing on behavior. The hAPP/Tau mouse described here displays pathology reminiscent of the human AD condition and serves as a new model for researchers to assess how both amyloid and tau pathology can together impact the brain and behavior.