This proposal is submitted in response to NOT-AG-18-039 ?Alzheimer's-focused administrative supplements for NIH grants that are not focused on Alzheimer's disease? to request a supplement to 1R01NS103529 ?Mechanisms Underlying TAAR1-induced Wakefulness and REM Sleep Suppression?. Over the past decade, there has been an increasing appreciation of sleep quality as a risk factor for the development of Alzheimer's disease. Animal studies have established that experimentally-induced sleep disruption can accelerate beta-amyloid (A?) plaque formation in mouse brain; conversely, pharmacological interventions to improve sleep quality can delay plaque formation. These observations have stimulated pharmacological studies to improve the quality of both sleep and wakefulness to potentially mitigate the deleterious effects of A? deposition. Wakefulness-promoting strategies have the dual goals of enhancing cognitive performance and, by consolidating prior wakefulness, improving sleep quality by increasing homeostatic sleep drive. We have previously shown that activation of Trace Amine-associated receptor 1 (TAAR1) has remarkable wake-promoting effects in rats, mice and non-human primates (NHPs) as well as pro- cognitive effects in rats and NHPs. We hypothesize that TAAR1 activation will promote wakefulness, improve sleep quality by increasing homeostatic sleep drive, and enhance cognitive performance in hAPP- overexpressing J20 mice, a well-studied mouse model of Alzheimer's disease (AD) that exhibits profound EEG dysregulation and epileptiform activity. To test this hypothesis, we will first determine whether sleep homeostasis is disrupted in hAPP-overexpressing J20 mice. Since it is unknown whether these mice exhibit either basal or homeostatic sleep deficits, we will characterize baseline and recovery sleep and conduct quantitative EEG (qEEG) analyses in J20 mice from pre- to post-plaque deposition stages. We then evaluate whether decreasing monoaminergic and glutamatergic tone via TAAR1 agonism will improve sleep/wake and EEG synchronization in J20 mice. Lastly, we will determine whether partial or full TAAR1 agonism ameliorates the well-established spatial memory deficits in this strain. Together, these Aims will enable us to determine whether the J20 AD mouse model has a deficit in basal sleep/wake and/or homeostatic sleep regulation in conjunction with its well-established cognitive deficits, and whether the dysregulated EEG and cognitive deficits can be normalized by TAAR1 agonism. These studies will provide the basal information that can lead to future determination of whether hippocampal network dynamics are disturbed across arousal states in this AD model.
Over the past decade, there has been an increasing appreciation of sleep quality as a risk factor for the development of Alzheimer's disease (AD). These observations have stimulated pharmacological studies to improve the quality of both sleep and wakefulness as a strategy that may mitigate the deleterious effects of beta-amyloid (A?) plaque deposition in AD. We have previously shown that activation of Trace Amine- associated receptor 1 (TAAR1) has remarkable wake-promoting effects in rats, mice and non-human primates as well as pro-cognitive effects in rats and primates. We will test the hypothesis that TAAR1 activation will promote wakefulness, improve sleep quality by increasing homeostatic sleep drive, and enhance cognitive performance in a mouse model of AD that exhibits profound EEG dysregulation and epileptiform activity.
