| dc.description.abstract | An estimated 46.8 million people are living with dementia, and those numbers are expected to rise to 74.7 million by 2030. Alzheimer's disease (AD) is the most common underlying cause of dementia and accounts for up to 70% of dementia cases. AD is a chronic neurodegenerative disorder characterized by aggregation and accumulation of beta-amyloid (A-beta) peptides, resulting in neuron loss and eventually cognitive decline. The microglial cells of AD patients become dysfunctional and less able to clear A-beta from the blood brain barrier (BBB), but maintain their ability to detect A-beta peptides and produce proinflammatory cytokines in response. As a result, AD patients experience a self-perpetuating condition of neuroinflammation, resulting in accumulation of A-beta and eventually cognitive deficits. These pathological alterations seen in AD patients are similar to those induced by injections of lipopolysaccharide (LPS). Additionally, both AD patients and mice injected with LPS experience reduced durations of rapid eye movement (REM) sleep and enhanced duration of non-REM sleep. REM sleep plays an essential role in memory consolidation and non-REM sleep plays an essential role in the recovery from A-beta accumulation that occurs during wakefulness. The rising number of individuals who are receiving insufficient sleep may fail to receive these restorative functions provided by sleep. As a result, failing to obtain sufficient sleep could increase an individual's risk for developing dementia and eventually AD. The goal of this study is to examine this possibility further by investigating the effects of chronic mild SR alone and in the presence of an inflammatory insult (LPS), on cognition and hippocampal A-beta. It is hypothesized that chronic mild sleep restriction (SR) will lead to cognitive deficits and increased levels of hippocampal A-beta. It is also hypothesized that SR, following repeated LPS injections, will lead to greater cognitive deficits and higher levels of hippocampal A-beta than exposure to LPS or SR may induce alone. To test these hypotheses, fifty-five 4-6-month-old C57BL/6J mice were divided into SR, large cage control (LCC), and home cage control (HCC) groups. SR was achieved using the modified multiple platform method (MMPM), which deprived mice of REM sleep 10 hours every day for 6 weeks. LPS injections were administered during the last 7 days of the experiment. Cognition was examined using contextual fear conditioning (CFC) and A-beta was quantified using A-beta-x-42 ELISA. The results indicate that SR failed to significantly increase hippocampal A-beta and cognitive deficits, as described in previous studies. LPS also failed to alter hippocampal A-beta and cognitive deficits, as previously demonstrated in our lab. As a result, the data presented was unable to provide a firm conclusion on the effects of chronic mild SR following repeated endotoxin exposure on AD pathology. This data draws attention to the lack of consistency among the effects of SR and LPS on A-beta. Since this study was unable arrive at an answer to the question, we set out to investigate, it is necessary to explore the relationship between SR following LPS exposure in future studies. Understanding how sleep and LPS impact the onset and progression of AD can aid in the development of strategies that may one day decrease its prevalence. | |
