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Front. Aging Neurosci. | doi: 10.3389/fnagi.2018.00382

A novel hAPP/htau mouse model of Alzheimer’s disease: Inclusion of APP with tau exacerbates behavioral deficits and zinc administration heightens tangle pathology

 Stephen L. Lippi1, 2, Meghann L. Smith2, 3 and  Jane M. Flinn2*
  • 1Angelo State University, United States
  • 2George Mason University, United States
  • 3National Institutes of Health (NIH), United States

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 < .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 < .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 < .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 < .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 < .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.

Keywords: mouse models, Amyloid, Tau (MAPT), Barnes Maze, Zinc, Behavior

Received: 14 Aug 2018; Accepted: 31 Oct 2018.

Edited by:

Ruben Vidal, Indiana University, Purdue University Indianapolis, United States

Reviewed by:

David Morgan, College of Human Medicine, Michigan State University, United States
Adrian L. Oblak, School of Medicine, Indiana University Bloomington, United States  

Copyright: © 2018 Lippi, Smith and Flinn. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Jane M. Flinn, George Mason University, Fairfax, 22030, Virginia, United States,