Author ORCID Identifier
https://orcid.org/0000-0003-3242-9314
Date Available
7-30-2026
Year of Publication
2024
Degree Name
Doctor of Philosophy (PhD)
Document Type
Doctoral Dissertation
College
Engineering
Department/School/Program
Biomedical Engineering
First Advisor
Dr. Sridhar Sunderam
Abstract
It is well established that sleep plays an important role in Alzheimer’s disease (AD) pathology. There is growing evidence that sleep issues may accelerate AD pathology by interrupting the physiological clearance of amyloid‐β (Aβ) from the brain, which mainly occurs in normal sleep. As the over-accumulation of amyloid‐β (Aβ) is believed to lead the cascade effect that eventually causes neurodegeneration in AD patients, development of therapeutic strategies for improving sleep quality may help slow disease progression. It is well documented that the composition and dynamics of sleep are sensitive to changes in ambient temperature. We therefore developed a sleep enhancement (SE) protocol based on thermoneutral warming to examine the effect on AD pathology in mouse models of AD. We started with a study on 12-month-old female 3xTg-AD mice (n = 16) instrumented for EEG/EMG analysis of sleep. 3xTg-AD mice were exposed to thermoneutral temperatures during the inactive light period over four weeks, and Aβ pathology and sleep metrics derived from polysomnography compared to those of controls (n = 8) that remained at normal housing temperature (22⁰C) during the same period. The treated group experienced greater proportions of slow wave sleep (SWS)—i.e., epochs of elevated 0.5-2 Hz slow wave activity during non-rapid eye movement (NREM) sleep—compared to controls. Assays performed on mouse brain tissue harvested at the end of the experiment showed that exposure to thermoneutral temperatures significantly reduced levels of diethylamine -soluble (but not formic acid-soluble) Aβ40 and Aβ42 in the hippocampus, though not in the cortex. Furthermore, the reduction in amyloid deposition was negatively correlated with SWS in the pooled cohort (n = 11). However, it can be argued that the change in Aβ accumulation is mediated by temperature-related effects on biological processes other than sleep. To address this question, we designed a protocol for bidirectional sleep manipulation that combines sleep disruption (SD) with the SE intervention. This new SE×SD protocol involves groups of mice being exposed to thermoneutral temperature during the day without (SE) or with (SE+SD) intermittent sensory stimulation over four weeks and compared them to controls (CTRL) that remained at vivarium temperature (22⁰C).
The SE×SD experiment was first tested in mice implanted for EEG/EMG monitoring of sleep in a relatively small sample size (33 treated, 21 with usable EEG signals). However, though there were some changes in SWS with treatment, no differences between groups were significant. Immunohistochemical (IHC) imaging of the cortex also showed that several mice had inflammatory responses to the EEG electrodes that would confound the interpretation of treatment effects on pathology. To improve on this test and gain usable tissue for bioassays, we conducted a second SE×SD experiment using a custom-built cage system in which sleep was monitored by piezoelectric motion sensors without invasive EEG/EMG analysis. The piezoelectric sensors could be used to distinguish sleep from wakefulness but not NREM from REM sleep or SWS within NREM. The SE group (n=8) spent more time in sleep relative to a baseline, while SD (n=12) and SE+SD (n=12) both spent less, compared to the CTRL group (n=8). While this demonstrates that the SE×SD protocol has the desired effect on mouse sleep, results from IHC and biochemical assays would further ascertain whether amyloid pathology is correlated with – and mediated by – changes in sleep.
In summary, our findings show that thermoneutral warming is an effective way of improving sleep in mice. The thermoneutral warming treatment in mouse model of AD also leads to a reduction in Aβ accumulation. These findings reveal a connection between sleep, AD and thermoneutral warming. A new AD treatment strategy different from the traditional pharmaceutical approaches could perhaps be developed based on this connection. Future directions of this study will be on the development of better thermoneutral warming-based sleep enhancement protocols, for example a closed loop system that only targets NREM sleep. Finally, correlation of sleep changes induced by the SExSD protocol with immunohistochemical analysis of pathology would help better establish the connection between sleep and AD.
Digital Object Identifier (DOI)
https://doi.org/10.13023/etd.2024.305
Funding Information
This study was supported by the National Institutes of Health Grant (no.: R01AG068215) in 2018
Recommended Citation
Wang, Jun, "RELATING TEMPERATURE, SLEEP, AND PATHOLOGY IN MOUSE MODELS OF ALZHEIMER'S DISEASE" (2024). Theses and Dissertations--Biomedical Engineering. 82.
https://uknowledge.uky.edu/cbme_etds/82
