GABA-positive astrocytosis in sleep-promoting areas associated with sleep disturbance in 5XFAD mice

Abstract

This dissertation investigates the potential connections between amyloid beta (Aβ) accumulation, reactive astrocytosis, and sleep disturbances in the progression of Alzheimer's disease (AD). It comprises several chapters that delve into the current understanding of sleep and AD, examine factors contributing to sleep deterioration throughout disease progression, and explore the pathological changes in sleep-promoting regions in AD. A comprehensive approach is employed, combining in vivo and in vitro techniques to examine the underlying mechanisms and their implications on sleep quality in AD. The study outlined in this dissertation utilized 24-hour electroencephalography (EEG) recordings of 5XFAD mice at 3, 6, and 10 months to characterize sleep disturbances and assess the impact of age on sleep behavior in a mouse model of AD. Subsequently, an examination of sleep-promoting neurons in key brain regions, including neuronal nitric oxide synthase-containing (nNOS) neurons in the cortex, galaninergic neurons in the ventrolateral preoptic area (VLPO), and cholinergic neurons in the laterodorsal tegmentum (LDT), were conducted using immunohistochemical analysis of various markers such as thioflavin-S, glial fibrillary acidic protein (GFAP), gamma-aminobutyric acid (GABA), and GABAA receptors containing the delta subunit (GABRD). The analysis uncovers a correlation between sleep disturbances and the total number of GFAP-positive astrocytes, as well as the proportion of GFAP- and GABA-positive astrocytes in all sleep-promoting regions investigated. These findings suggest that astrocyte reactivity may contribute to the sleep disturbances observed in the progression of AD. Moreover, the presence of GABRD in sleep-promoting neurons highlights the potential involvement of extrasynaptic GABAergic signaling in the sleep abnormalities associated with AD. The results reveal that neurotoxic reactive astrocytosis in non-rapid eye movement (NREM) and rapid eye movement (REM) sleep-promoting regions correlates with sleep disturbances in 5XFAD mice. This suggests a potential role of abnormal astrocytic GABA in the sleep disturbances observed in Alzheimer's disease. The findings provide valuable insights into the intricate relationship between sleep disturbances and AD pathology, paving the way for future research on targeted interventions for sleep-related issues in AD patients. Furthermore, this dissertation underscores the importance of understanding the complex interplay between neuronal and glial cells in the context of sleep and neurodegenerative diseases, potentially opening up new avenues for therapeutic development.