Assessing Sex-Specific Circadian, Metabolic, and Cognitive Phenotypes in the AβPP/PS1 and APP^NL-F/NL-F Models of Alzheimer’s Disease

Article type: Research Article

Authors: Britz, Jesse^a | Ojo, Emmanuel^a | Dhukhwa, Asmita^a | Saito, Takashi^b | Saido, Takaomi C.^c | Hascup, Erin R.^{a; d} | Hascup, Kevin N.^{a; d; e} | Tischkau, Shelley A.^{a; e; *}

Affiliations: [a] Department of Pharmacology, Southern Illinois University School of Medicine, Springfield, IL, USA | [b] Department of Neurocognitive Science, Institute of Brain Science, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan | [c] Laboratory for Proteolytic Neuroscience, RIKEN Center for Brain Science, Wako, Saitama, Japan | [d] Department of Neurology, Dale and Deborah Smith Center for Alzheimer’s Research and Treatment, Southern Illinois University School of Medicine, Springfield, IL, USA | [e] Department of Medical Microbiology, Immunology and Cell Biology, Southern Illinois University School of Medicine, Springfield, IL, USA

Correspondence: [*] Correspondence to: Shelley A. Tischkau, PhD, 801 N. Rutledge, Room 3289, Springfield, IL 62794-9629, USA. Tel.: +1 217 840 6724; E-mail: [email protected].

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.

Keywords: Alzheimer’s disease, amyloid-β, arginine vasopressin, circadian rhythm, cognition, glial fibrillary acidic protein, metabolism, vasoactive intestinal peptide

DOI: 10.3233/JAD-210629

Journal: Journal of Alzheimer's Disease, vol. 85, no. 3, pp. 1077-1093, 2022