Experimental diffuse brain injury and a model of Alzheimer's disease exhibit disease-specific changes in sleep and incongruous peripheral inflammation

Abstract

Elderly populations (≥65 years old) have the highest risk of developing Alzheimer's disease (AD) and/or obtaining a traumatic brain injury (TBI). Using translational mouse models, we investigated sleep disturbances and inflammation associated with normal aging, TBI and aging, and AD. We hypothesized that aging results in marked changes in sleep compared with adult mice, and that TBI and aging would result in sleep and inflammation levels similar to AD mice. We used female 16-month-old wild-type (WT Aged) and 3xTg-AD mice, as well as a 2-month-old reference group (WT Adult), to evaluate sleep changes. WT Aged mice received diffuse TBI by midline fluid percussion, and blood was collected from both WT Aged (pre- and post-TBI) and 3xTg-AD mice to evaluate inflammation. Cognitive behavior was tested, and tissue was collected for histology. Bayesian generalized additive and mixed-effects models were used for analyses. Both normal aging and AD led to increases in sleep compared with adult mice. WT Aged mice with TBI slept substantially more, with fragmented shorter bouts, than they did pre-TBI and compared with AD mice. However, differences between WT Aged and 3xTg-AD mice in immune cell populations and plasma cytokine levels were incongruous, cognitive deficits were similar, and cumulative sleep was not predictive of inflammation or behavior for either group. Our results suggest that in similarly aged individuals, TBI immediately induces more profound sleep alterations than in AD, although both diseases likely include cognitive impairments. Unique pathological sleep pathways may exist in elderly individuals who incur TBI compared with similarly aged individuals who have AD, which may warrant disease-specific treatments in clinical settings.

Keywords: Alzheimer's disease; RRID:AB_10640819; RRID:AB_11203896; RRID:AB_2340846; RRID:AB_2340855; RRID:AB_2562218; RRID:AB_2562351; RRID:AB_2722581; RRID:AB_2732058; RRID:AB_2734548; RRID:AB_312791; RRID:AB_312977; RRID:AB_839504; RRID:SCR_00044; RRID:SCR_001905; RRID:SCR_004633; aging; blood cytokines; monocytes; sleep; traumatic brain injury.