Autophagy-Enhancers to reduce sleep disturbances: a combined approach

自噬增强剂减少睡眠障碍：综合方法

• 批准号: 508402643
• 负责人: Professorin Dr. Agnes Flöel
• 金额: --
• 依托单位: Klinik und Poliklinik für Neurologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/508402643?language=en
• 关键词: Autophagy; Enhancers; reduce; sleep; disturbances

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.

阿尔茨海默病 (AD) 是一种进行性神经退行性疾病，会导致严重的认知障碍。迄今为止，AD 背后复杂的病理生理学尚未完全了解。然而，众所周知，失眠是 AD 的危险因素，而睡眠障碍是 AD 的早期组成部分。睡眠对于巩固记忆至关重要。与陈述性记忆巩固相关的一个重要的神经生理学机制是慢波睡眠（SWS）。与没有神经退行性疾病的同龄个体相比，患有轻度认知障碍（MCI）或 AD 所致痴呆的患者的特征是 SWS 比例下降更快。此外，研究表明，与年龄相关的睡眠障碍与胰岛素敏感性下降和神经肽 Y (NPY) 信号传导受损有关。由于痴呆阶段很难开发出治愈性疗法，AD治疗研究的重点已部分转移到早期阶段，即在MCI阶段或更早寻找疾病缓解剂和介入方法来维持大脑健康和认知能力。一种有前途的疾病缓解剂可能是聚胺亚精胺。先前的研究表明，增加外源性亚精胺有益于衰老动物和人类的整体健康、T 细胞功能和记忆维持的各个方面。此外，还发现补充亚精胺（Spd-S）可以防止果蝇睡眠模式与年龄相关的变化。然而，迄今为止，尚不清楚亚精胺对大脑健康的有益作用是否（部分）是通过睡眠质量的变化以及胰岛素-葡萄糖代谢的相关变化来介导的。该项目的目标是确定 Spd-S 对睡眠生理学和睡眠依赖性记忆巩固的影响。此外，还将在果蝇模型和人类中系统地研究这种关系的机制，特别是胰岛素-葡萄糖代谢、NPY信号传导以及与自噬标记物的关系。在动物模型中，自噬在睡眠控制中的作用将在中年、老年和 AD 果蝇中进行基因测试。此外，还将研究与 Spd-S 的睡眠保护作用相关的代谢变化。在人类中，一项干预研究将调查与安慰剂补充剂相比，Spd-S 改善 MCI 中 SWS 和睡眠相关记忆巩固的能力。拟议的项目将深入了解 Spd-S、细胞自主机制（如自噬）、非细胞自主机制（如 NPY、睡眠和记忆）之间的潜在关系。此外，通过 Spd-S 改善睡眠生理和记忆巩固可能会导致临床相关的衰老过程中大脑健康的保存。