Autophagy-Enhancers to reduce sleep disturbances: a combined approach

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Alzheimer's disease (AD) is a progressive neurodegenerative disease that leads to devastating cognitive impairment. To date, the complex pathophysiology underlying AD is not fully understood. However, it is known that insomnia is a risk factor for AD and that sleep disturbances are an early component of AD. Sleep is essential for memory consolidation. An important neurophysiological mechanism related to declarative memory consolidation is slow-wave sleep (SWS). Patients with mild cognitive impairment (MCI) or dementia due to AD are characterized by a more rapid decline in the proportion of SWS compared with individuals of the same age without neurodegenerative disease. In addition, studies have shown that age-related sleep disorders are associated with decreased insulin sensitivity and impaired neuropeptide Y (NPY) signaling. Due to the difficulty to develop curative therapies in the dementia stage, the focus of therapy research for AD has in part shifted to the early stages, i.e., finding disease-modifying agents and interventional approaches to maintain brain health and cognitive performance in the MCI stage or even earlier. One promising disease-modifying agent may be the polyamine spermidine. Previous research has shown that increased exogenous spermidine benefits various aspects of general health, T-cell function, and memory maintenance in aging animals and humans. Additionally, spermidine supplementation (Spd-S) was found to protect against age-related changes in sleep patterns in Drosophila fruit flies. However, to date, it is not known whether the beneficial effects of spermidine on brain health are mediated (in part) by changes in sleep quality and associated changes in insulin-glucose metabolism. The goal of the proposed project is to determine the effects of Spd-S on sleep physiology and sleep-dependent memory consolidation. In addition, the mechanisms underlying this relationship will be systematically investigated in both fly models and humans, particularly insulin-glucose metabolism, NPY signaling, and the relationship with markers of autophagy. In animal models, the role of autophagy in sleep control will be genetically tested in middle-aged, old and AD flies. In addition, the metabolic changes responsible for the sleep protective effect of Spd-S will be investigated. In humans, an intervention study will investigate the ability of Spd-S to improve SWS and sleep-related memory consolidation in MCI compared to placebo supplementation. The proposed project will provide insight into the potential relationship between Spd-S, cell autonomous mechanisms such as autophagy, non-cell autonomous mechanisms such as NPY, sleep and memory. Moreover, improvement of sleep physiology and memory consolidation via Spd-S might lead to clinically relevant preservation of brain health in aging.