The Effects of Chronic Zinc Supplementation on Behavior and Tauopathy in an Alzheimer's Disease Mouse Model Containing Both APOE4 and Tau

Aaron B. Booth

Advisor: Jane M Flinn, PhD, Department of Psychology

Committee Members: Tyler Shaw, Jennifer Brielmaier

David J. King Hall, #2073A
November 22, 2024, 12:30 PM to 02:30 PM

Abstract:

Alzheimer’s Disease (AD) is a neurological disease characterized by two major biological components; amyloid beta (abeta) and hyperphosphorylated tau (p-tau). However, it is thought that early-onset and late-onset AD may differ in terms of how p-tau aggregates, with p-tau aggregation primarily being caused by abeta buildup in early-onset AD, and p-tau aggregation being caused by both abeta and a system independent of abeta buildup in late-onset AD. It is thought that this p-tau buildup independent of abeta may be due to the APOE4 allele, a major genetic risk factor of late-onset AD. While the relationship between APOE4 and abeta has been well researched, the relationship between APOE4 and p-tau in the absence of abeta has been both inconsistent and lacks behavioral results. This study examined an APOE4 x Tau mouse model to better understand this interaction independent of systems involving abeta. Additionally, the effects of zinc were examined in this mouse model. Previous research suggests that zinc exacerbates the effects of both abeta and tau in other mouse models, however, there is limited research in how zinc and copper interact with APOE4. For this study, mice were placed in 8 groups; 4 genotypes (WT, E4, Tau, E4 x Tau), 2 metal ion supplements (none, zinc). Behavioral tests were examined age 3 and 6 months to measure spatial memory (Morris Water Maze), risk taking (Elevated Zero), anxiety (Open Field), activities of daily living (Nesting & Burrowing), and circadian activity (Wheel Running). Brains were removed and analyzed by various morphological tests including histological staining, Western Blot analysis, and Zinpyr-1. Results indicated that mouse models containing tau, with or without E4, show impairments in behavior as well as morphological abnormalities which match those impairments. However, while these impairments and morphological abnormalities are still present, they are reduced in a mouse model with both APOE4 and Tau compared to a mouse model containing only Tau. This indicates that, while APOE4 is a risk factor for late-onset Alzheimer’s, APOE4 in the absence of Abeta may actually play a beneficial effect. There was no difference in groups based on zinc supplementation.