Abstract
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.
Highlights
Alzheimer’s disease (AD) is a neurodegenerative disorder affecting the lives of an estimated 5.7 million individuals in the United States; this estimate is projected to more than double by the year 2050 (Alzheimer’s Association, 2018)
We have characterized a novel dual Tg mouse with mutations in human APP and tau. This was accomplished through a range of behavioral tasks at two time points and the assessment of plaque and tangle pathology
Dual Tg mice showed an increase in tangle pathology compared to htau mice in the HP and performed significantly worse in behavioral tasks
Summary
Alzheimer’s disease (AD) is a neurodegenerative disorder affecting the lives of an estimated 5.7 million individuals in the United States; this estimate is projected to more than double by the year 2050 (Alzheimer’s Association, 2018). There is currently no cure for AD, only therapeutics that temporarily mitigate symptoms With this in mind, researchers in the field have formulated numerous hypotheses, speculating which protein species may be playing more prominent roles in AD’s progression and the best way to combat it. Tau may increase the toxic effect of amyloid (Ittner and Götz, 2011). Another theory, the metal hypothesis of AD (Bush, 2013; Adlard and Bush, 2018) is based on the dyshomeostasis of metal species, including Zn, seen in AD. RTg4510 (Tau P301L) Alzforum.org/researchmodels/rtgtaup301l4510 Ramsden et al, 2005; Santacruz et al, 2005 3xTg-AD Alzforum.org/research-models/3xtg Oddo et al, 2003. JNPL3 × Tg2576 Alzforum.org/researchmodels/tg2576 alzforum.org/researchmodels/jnpl3p301l Lewis et al, 2001 (Tg2576 × JNPL3) VLW × Tg2576 Lim et al, 2001 (VLW mice) Pérez et al, 2005 (VLW × Tg2576) Ribé et al, 2005 (VLW × Tg2576)
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