THE CONSEQUENCES OF SLEEP DISRUPTION IN ALZHEIMER’S DISEASE PROGRESSION AND TREATMENT

Sleep is an essential physiological behavior that supports cognitive function. Deficits in sleep behavior throughout the lifespan contributes to various neurodevelopmental and neurodegenerative diseases. In Alzheimer’s disease (AD), a devastating neurodegenerative disorder, patients experience accelerated sleep loss which can be correlated with AD onset and contribute to AD progression. Tau is an axonal microtubule stabilizing protein that forms aggregates and contributes to the cognitive decline, synapse loss and neuronal death seen in AD. Recently, Tau has been shown to mislocalize and aggregate in synapses which may impair synapse weakening during sleep – likely responsible for forming the restorative benefits of sleep. Currently there are no therapies to alleviate the negative consequences of tau pathology in AD. Endocannabinoids provide an intriguing avenue for therapeutic intervention because of their role in promoting anti-inflammatory signaling and sleep. Therefore, this dissertation will highlight experiments aimed at understanding the relationship between sleep disruption and tau pathology at the synapse. We will test the link between sleep disruption and tau aggregation and highlight the therapeutic window targeting endocannabinoid signaling during sleep in advance of Tau pathology and cognitive decline. I hypothesize that sleep disruption occurs early in AD progression and is a major driver of subsequent tau mislocalization and aggregation, and cognitive decline. In order to test this hypothesis, I utilized P301S (PS19) transgenic mice that overexpress aggregation-prone human Tau. These animals show age-dependent cognitive decline and Tau accumulation. In chapter 2, I will discuss the role for eCBs in sleep in development. In chapter 3, I will discuss the relationship between tau pathology at the synapse and sleep. Finally in chapter 4, I will discuss whether genetic regulation of synaptic eCBs can improve sleep in PS19 mice. Together these studies will provide a deeper understanding of the behavioral and molecular changes that occur during abnormal sleep in AD and highlight endocannabinoids as a suitable signaling pathway for enhancing the restorative benefits of sleep.