SLEEP-DEPENDENT MICROGLIAL CALCIUM DYNAMICS IN ALZHEIMER’S DISEASE MOUSE MODELS

Sleep is becoming increasingly recognised to be associated with Alzheimer’s disease (AD), yet their relationship remains to be determined. It is known that microglia play a role in both sleep and AD. For example, microglia alter their intracellular calcium levels across the sleep-wake cycle and are involved in neuroinflammatory events throughout AD. However, little is understood about the influence of sleep loss and AD pathology on microglial calcium activity. Here we investigate microglial calcium dynamics across the sleep-wake cycle in AD mouse models in vivo. We used a triple transgenic approach to express a genetically encoded calcium indicator, jGCaMP8s, in microglia. We crossed either 5xFAD or App^NL-G-F AD mouse models with Tmem119-CreER2 and Cre-dependent jGCaMP8s mice, where tamoxifen was administered to induce recombination. Next, we chronically implanted electrophysiological electrodes and a tapered optical fibre into hippocampal regions. We report that both 5xFAD;Tmem119-CreER2;jGCaMP8s and App^NL-G-F;Tmem119-CreER2;jGCaMP8s mice show brain-wide jGCaMP8s expression in Iba1-positive microglia. We also found that microglial calcium dynamics fluctuate across the sleep-wake cycle to varying degrees across AD models. Further characterisation of state-dependent calcium dynamics in microglia will provide insight into how sleep and AD pathogenesis are related to homeostatic microglial calcium activity. Specifically, determining if sleep loss and AD pathology can contribute to dysregulation of microglial calcium dynamics and their neuroprotective functions is crucial. Consequently, this could provide opportunities to develop a novel intervention strategy for AD.