Hyperphosphorylated tau protein is a key pathology in Alzheimer’s disease (AD), frontotemporal dementia, chronic traumatic encephalopathy, and Parkinson’s disease. The essential trace element zinc exacerbates tauopathy in vitro as well as in a Drosop

There is considerable evidence suggesting that metals play a central role in the pathogenesis of Alzheimer's disease. Reports suggest that elevated dietary metals may both precipitate and potentiate an Alzheimer's disease phenotype. Despite this, the

Disruptions to daily living, inflammation, and astrogliosis are characteristics of Alzheimer's disease. Thus, circadian rhythms, nest construction, IL-1β and TNF-α, and glial fibrillary acidic protein (GFAP) were examined in a mouse model developed t

Much of the research in Alzheimer’s disease (AD) that uses mouse models focuses on the early-onset form of the disease, which accounts for less than 5% of cases. In contrast, this study used a late-onset AD model to examine the interaction between increased dietary zinc (Zn) and the apolipoprotein E (ApoE) gene. ApoE ε4 is overrepresented in late-onset AD and enhances Zn binding to amyloid-β (Aβ). This study sought to determine if elevated dietary Zn would impair spatial memory in CRND8 mice (CRND8), as well as mice who carry both the mutated human APP and ApoE ε4 genes (CRND8/E4). Mice were provided with either lab tap water or water enhanced with 10 ppm Zn (ZnCO3) for 4 months. At 6 months of age, spatial memory was measured by the Barnes maze. CRND8 mice exhibited significant memory deficits compared to WT mice, as shown by an increased latency to reach the escape box. For the CRND8/E4, but not the CRND8 mice, those given Zn water made significantly more errors than those on lab water. During the probe trial for the WT group, those on Zn water spent significantly less time in the target quadrant than those on lab water. These data suggest that increased dietary Zn can significantly impair spatial memory in CRND8/E4. WT mice given Zn water were also impaired on the 24-hour probe trial when compared to lab water WTs. Within the CRND8/E4 group only, levels of soluble Aβ were significantly correlated with average primary latencies. Within the Zn-treated CRND8/E4 group, there was a significant correlation between insoluble Aβ and average primary errors. Levels of the zinc transporter 3, ZnT3, were negatively correlated with soluble Aβ (p < .01). These findings are particularly relevant because increased intake of dietary supplements, such as Zn, are common in the elderly—a population already at risk for AD. Given the effects observed in the CRND8/E4 mice, ApoE status should be taken into consideration when evaluating the efficacy of therapies targeting metals.

The brains of those with Alzheimer's disease have amyloid and tau pathology; thus, mice modeling AD should have both markers. In this study, we characterize offspring from the cross of the J20 (hAPP) and rTg4510 (htau) strains (referred to as dual Tg). Behavior was assessed at both 3.5 and 7 months, and biochemical differences were assessed at 8 months. Additionally, mice were placed on zinc (Zn) water or standard lab water in order to determine the role of this essential biometal. Behavioral measures examined cognition, emotion, and aspects of daily living. Transgenic mice (dual Tg and htau) showed significant deficits in spatial memory in the Barnes Maze at both 3.5 and 7 months compared to controls. At 7 months, dual Tg mice performed significantly worse than htau mice (p < 0.01). Open field and elevated zero maze (EZM) data indicated that dual Tg and htau mice displayed behavioral disinhibition compared to control mice at both 3.5 and 7 months (p < 0.001). Transgenic mice showed significant deficits in activities of daily living, including burrowing and nesting, at both 3.5 and 7 months compared to control mice (p < 0.01). Dual Tg mice built very poor nests, indicating that non-cognitive tasks are also impacted by AD. Overall, dual Tg mice demonstrated behavioral deficits earlier than those shown by the htau mice. In the brain, dual Tg mice had significantly less free Zn compared to control mice in both the dentate gyrus and the CA3 of the hippocampus (p < 0.01). Dual Tg mice had increased tangles and plaques in the hippocampus compared to htau mice and the dual Tg mice given Zn water displayed increased tangle pathology in the hippocampus compared to htau mice on Zn water (p < 0.05). The dual Tg mouse described here displays pathology reminiscent of the human AD condition and is impaired early on in both cognitive and non-cognitive behaviors. This new mouse model allows researchers to assess how both amyloid and tau in combination impact behavior and brain pathology.