Astroglial mechanisms in sleep homeostasis

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Summary Our parent grant NS114780 will determine cellular and molecular signaling pathways in astrocytes important in mammalian sleep regulation. We now extend our approach to neurodegenerative diseases, with a focus on mouse models of Alzheimer’s. Sleep may play an important role in the etiology and progression of neurodegenerative disease. Abnormal sleep is a common symptom of many neurodegenerative diseases including Alzheimer’s. Sleep also influences several neurological processes that if perturbed may contribute to cognitive decline and dementia. Among these are synaptic morphology/plasticity, immune response/neuroinflammation, brain metabolism and protein clearance. Therefore, understanding how sleep and sleep loss impact the diseased brain may provide new insights into Alzheimer’s and related diseases. This requires an understanding of how different classes of brain cells operate during sleep. The glial cells known as astrocytes are particularly important to examine in this context. Astrocytes mediate several processes dysregulated in Alzheimer’s (e.g. synaptic pruning, neuronal metabolism and removal of plaque proteins and are abnormally hyper-reactive in neurodegenerative disease (as measured by increased intracellular Ca2+. Astrocyte hyper-reactivity may in turn disrupt these normal processes vital to brain function. We have shown that astrocytes play central roles in mammalian sleep regulation. We have also recently demonstrated that sleep normally reduces (clears) astrocyte intracellular Ca2+ concentrations that accumulate during wakefulness [18]. We hypothesize that in Alzheimer’s the regulation of intracellular Ca2+ in astrocytes during sleep is abnormal leading to astrocytic hyper-reactivity. We will test this hypothesis by Impact: Sleep and astrocytes are implicated in neurodegenerative diseases like Alzheimer’s. Recent findings from our laboratory indicate that astrocytes influence sleep. This indicates that astrocytes may mediate important sleep functions that are relevant to neurodegenerative diseases. The requisite step to exploring this possibility is to examine the activity of these glial cells during sleep in mouse models of neurodegenerative disease. Our hypothesis is that sleep loss results in a persistent activation of astrocytes in neurodegenerative disease, which in turn could lead to neuronal cell death. If true, our findings will be impactful because they will identify a heretofore poorly understood interaction between sleep and glia that can be leveraged for new therapeutic approaches to Alzheimer’s.