Jesse Britz1, Emmanuel Ojo1, Asmita Dhukhwa1, Takashi Saito2, Takaomi C Saido3, Erin R Hascup1,4, Kevin N Hascup1,4,5, Shelley A Tischkau1,5. 1. Department of Pharmacology, Southern Illinois University School of Medicine, Springfield, IL, USA. 2. Department of Neurocognitive Science, Institute of Brain Science, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan. 3. Laboratory for Proteolytic Neuroscience, RIKEN Center for Brain Science, Wako, Saitama, Japan. 4. Department of Neurology, Dale and Deborah Smith Center for Alzheimer's Research and Treatment, Southern Illinois University School of Medicine, Springfield, IL, USA. 5. Department of Medical Microbiology, Immunology and Cell Biology, Southern Illinois University School of Medicine, Springfield, IL, USA.
Abstract
BACKGROUND: Circadian disruption has long been recognized as a symptom of Alzheimer's disease (AD); however, emerging data suggests that circadian dysfunction occurs early on in disease development, potentially preceding any noticeable cognitive deficits. OBJECTIVE: This study compares the onset of AD in male and female wild type (C57BL6/J), transgenic (AβPP/PS1), and knock-in (APPNL-F/NL-F) AD mouse models from the period of plaque initiation (6 months) through 12 months. METHODS: Rhythmic daily activity patterns, glucose sensitivity, cognitive function (Morris water maze, MWM), and AD pathology (plaques formation) were assessed. A comparison was made across sexes. RESULTS: Sex-dependent hyperactivity in AβPP/PS1 mice was observed. In comparison to C57BL/6J animals, 6-month-old male AβPP/PS1 demonstrated nighttime hyperactivity, as did 12-month-old females. Female AβPP/PS1 animals performed significantly worse on a MWM task than AβPP/PS1 males at 12 months and trended toward increased plaque pathology. APPNL-F/NL-F 12-month-old males performed significantly worse on the MWM task compared to 12-month-old females. Significantly greater plaque pathology occurred in AβPP/PS1 animals as compared to APPNL-F/NL-F animals. Female AβPP/PS1 animals performed significantly worse than APPNL-F/NL-F animals in spatial learning and memory tasks, though this was reversed in males. CONCLUSION: Taken together, this study provides novel insights into baseline sex differences, as well as characterizes baseline diurnal activity variations, in the AβPP/PS1 and APPNL-F/NL-F AD mouse models.
BACKGROUND: Circadian disruption has long been recognized as a symptom of Alzheimer's disease (AD); however, emerging data suggests that circadian dysfunction occurs early on in disease development, potentially preceding any noticeable cognitive deficits. OBJECTIVE: This study compares the onset of AD in male and female wild type (C57BL6/J), transgenic (AβPP/PS1), and knock-in (APPNL-F/NL-F) AD mouse models from the period of plaque initiation (6 months) through 12 months. METHODS: Rhythmic daily activity patterns, glucose sensitivity, cognitive function (Morris water maze, MWM), and AD pathology (plaques formation) were assessed. A comparison was made across sexes. RESULTS: Sex-dependent hyperactivity in AβPP/PS1 mice was observed. In comparison to C57BL/6J animals, 6-month-old male AβPP/PS1 demonstrated nighttime hyperactivity, as did 12-month-old females. Female AβPP/PS1 animals performed significantly worse on a MWM task than AβPP/PS1 males at 12 months and trended toward increased plaque pathology. APPNL-F/NL-F 12-month-old males performed significantly worse on the MWM task compared to 12-month-old females. Significantly greater plaque pathology occurred in AβPP/PS1 animals as compared to APPNL-F/NL-F animals. Female AβPP/PS1 animals performed significantly worse than APPNL-F/NL-F animals in spatial learning and memory tasks, though this was reversed in males. CONCLUSION: Taken together, this study provides novel insights into baseline sex differences, as well as characterizes baseline diurnal activity variations, in the AβPP/PS1 and APPNL-F/NL-F AD mouse models.
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