Functional restoration of REM sleep fragmentation, hippocampal oscillatory activity and altered cholinergic signaling at presymptomatic stages of AD

Abstract Background Alzheimer’s disease (AD) is a severe neurodegenerative disorder that is hallmarked by the progressive accumulation of amyloid beta (Aβ) and tau proteins in the brain, leading to dementia. Sleep alterations occur at early stages of AD, before cognitive symptoms become apparent, which could play an important role in the pathophysiology and detection of AD. The current study aimed to evaluate how circadian rhythm, sleep macro-architecture and hippocampal oscillations are altered at pre-plaque and early-plaque stages of AD in TgF344-AD rats. Methods We performed 24-hour hippocampal electrophysiological measurements in TgF344-AD rats and wildtype littermates at pre- and early-plaque stages of AD, combined with histological analysis to evaluate histopathological alterations. Results We observed a differential impact of AD on rapid eye movement (REM) and non-REM (NREM) sleep. Circadian rhythmicity was intact and TgF344-AD rats did not show signs of NREM sleep fragmentation. We observed a significantly increased probability for shorter REM bouts, suggestive of REM sleep fragmentation, in TgF344-AD rats at the pre-plaque stage, which recovered at the early-plaque stage. In addition, we observed a significantly decreased theta-gamma coupling, a measure for task-related information ordering, at the pre-plaque stage, which was partially restored at the early-plaque stage. Moreover, theta-gamma coupling in the slow gamma range was significantly increased during the pre-plaque stage in TgF344-AD rats but returned to WT levels at the early-plaque stage. Interestingly, the partial compensation of hippocampal activity and REM sleep behavior coincided with an increased number of cholinergic synapses in the hippocampus during the early-plaque stage in TgF344-AD rats, suggestive of basal forebrain cholinergic compensation mechanisms. Conclusion The results from this study reveal early changes in sleep architecture and hippocampal function prior to Aß plaque deposition in AD. In addition, the current findings highlight the important role of the cholinergic system to compensate for AD-related network alterations. Network disturbances and sleep alterations are known to drive disease progression. Modulation of cholinergic signaling in early, presymptomatic AD might be a promising therapeutic strategy to alter disease progression by restoring network function and sleep architecture.