Sleep-dependent synaptic homeostasis in Alzheimer's disease

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PROJECT SUMMARY Sleep is an essential conserved behavior seen throughout life and is critical for brain health and maintenance of cognitive functions such as learning and memory. Sleep disruption is intimately linked to aging and believed to expose individuals to risk of developing Alzheimer's Disease (AD). After AD onset, continued decline in sleep amount/quality is associated with progressive decline in memory performance and cognition. Therefore, sleep disruption is a source of vulnerability as well as a potential therapeutic target to treat disease. A detailed molecular understanding of the ontogeny of sleep disruption could aid in the development of earlier diagnosis for AD, and in the identification of a therapeutic window for sleep-based medicines. We propose that promoting quality sleep during the early stages of AD may delay or halt progressive cognitive decline. However, the molecular basis of sleep's restorative processes that support cognition is poorly understood. Neuronal synapses are the structures responsible for forming and storing memories, particularly in forebrain structures such as the hippocampus and cortex. Our previous work shows that synapses are a major target for the restorative actions of sleep. We have shown that a form of synaptic plasticity called homeostatic scaling-down is engaged in the brain during sleep to support learning and memory functions. Synapse dysfunction is also known to occur early in AD progression when the Tau protein begins to accumulate in the brain. We hypothesize that aberrant synaptic Tau induces synaptic dysfunction by altering homeostatic scaling- down, leading to hyperexcitability and sleep disruption. Sleep disruption, and loss of the restorative homeostatic scaling, then accelerates disease pathology and cognitive decline. Preliminary findings indicate sleep disruption is an early phenotype in a Tau-based mouse model of AD. In aim 1 we examine the interaction between hallmark AD pathologies, amyloid plaques and Tau tangles, in driving sleep disruption, and examine the necessity of Tau or amyloid in sleep disruption onset. We test the relationship between sleep disruption and Tau pathology to establish sleep disruption as a biomarkers of pathology. In aim 2 we will use an in vitro model system to dissect the molecular mechanisms by which pathogenic Tau proteins affect synapse function. We will examine a particular cleaved Tau species known to accumulate at the synapse in AD human brain, and examine the effect of cleaved Tau on restorative homeostatic scaling-down. In aim 3 we will examine the sleep-dependent regulation of the endocannabinoid system during aging in AD model mice. Our preliminary data show that endocannabinoid signaling is engaged during homeostatic scaling in cultured neurons, and that regulation of endocannabinoids during the sleep-wake cycle is disrupted in AD model mice. We show that acutely increasing the endocannabinoid anandamide using a pharmacological approach promotes sleep in symptomatic AD mice. We will test the therapeutic efficacy of this sleep-promoting strategy in AD mice, with the translational implications of modifying sleep behavior to alter AD onset or progression in human patients.