文献类型：期刊文献

中文题名：睡眠剥夺促进阿尔茨海默病病理进程的分子机制

英文题名：Molecular Mechanisms Underlying Sleep Deprivation-induced Acceleration of Alzheimer’s Disease Pathology

作者：严思茹[1,2];蔡明扬[1,2];孙雅煊[1,2];霍清[1];戴雪伶[1,2]

第一作者：严思茹

机构：[1]北京联合大学生物化学工程学院食品与医药系,北京100023;[2]北京联合大学生物活性物质与功能食品北京市重点实验室,北京100023

第一机构：北京联合大学生物化学工程学院

年份：2025

卷号：52

期号：10

起止页码：2474-2485

中文期刊名：生物化学与生物物理进展

外文期刊名：Progress In Biochemistry and Biophysics

收录：;北大核心:【北大核心2023】；

基金：北京市自然科学基金(6164030);国家自然科学基金(11975048);北京联合大学教改项目(JY2023Y008)资助。

语种：中文

中文关键词：睡眠剥夺;阿尔茨海默病;β淀粉样蛋白;tau蛋白;神经炎症;突触可塑性

外文关键词：sleep deprivation;Alzheimer’s disease;amyloidβ-protein;tau protein;neuroinflammation;synaptic plasticity

摘要：睡眠剥夺(sleep deprivation,SD)指由于环境或自身原因导致的睡眠时间不足,是睡眠障碍的一种常见表现形式。近年来研究表明,SD不仅影响个体认知功能,还与阿尔茨海默病(Alzheimer’s disease,AD)的病理进程密切相关。AD患者中睡眠障碍的发生率较高,而SD也被认为是AD发生和进展的危险因素之一。SD通过多种分子与细胞机制促进AD的病理进展,其不仅破坏睡眠-觉醒周期与昼夜节律,还导致脑内β淀粉样蛋白(amyloidβ-protein,Aβ)的沉积;同时,SD还可促进tau蛋白的异常磷酸化,加剧神经纤维缠结的形成。此外,SD能够激活神经胶质细胞,如影响小胶质细胞和星形胶质细胞的吞噬活性,引发神经炎症反应,释放多种炎性细胞因子,进一步损害神经元功能。此外,SD还损害突触可塑性,影响突触相关蛋白的表达,并降低脑源性神经营养因子(brain-derived neurotrophic factor,BDNF)水平,进一步加重认知功能障碍与AD的神经退行性病变。最后,本文探讨了针对SD的多种干预策略,如褪黑素调节昼夜节律、食欲素受体拮抗剂改善睡眠质量、生酮饮食促进神经修复等在AD防治中的潜在应用价值,为开发基于睡眠调节的AD治疗新靶点提供了理论依据。
Sleep deprivation(SD)has emerged as a significant modifiable risk factor for Alzheimer’s disease(AD),with mounting evidence demonstrating its multifaceted role in accelerating AD pathogenesis through diverse molecular,cellular,and systemic mechanisms.SD is refined within the broader spectrum of sleep-wake and circadian disruption,emphasizing that both acute total sleep loss and chronic sleep restriction destabilize the homeostatic and circadian processes governing glymphatic clearance of neurotoxic proteins.During normal sleep,concentrations of interstitial Aβand tau fall as cerebrospinal fluid oscillations flush extracellular waste;SD abolishes this rhythm,causing overnight rises in soluble Aβand tau species in rodent hippocampus and human CSF.Orexinergic neurons sustain arousal,and become hyperactive under SD,further delaying sleep onset and amplifying Aβproduction.At the molecular level,SD disrupts Aβhomeostasis through multiple converging pathways,including enhanced production via beta-site APP cleaving enzyme 1(BACE1)upregulation,coupled with impaired clearance mechanisms involving the glymphatic system dysfunction and reduced Aβ-degrading enzymes(neprilysin and insulin-degrading enzyme).Cellular and histological analyses revealed that these proteinopathies are significantly exacerbated by SD-induced neuroinflammatory cascades characterized by microglial overactivation,astrocyte reactivity,and sustained elevation of pro-inflammatory cytokines(IL-1β,TNF-α,IL-6)through NF-κB signaling and NLRP3 inflammasome activation,creating a self-perpetuating cycle of neurotoxicity.The synaptic and neuronal consequences of chronic SD are particularly profound and potentially irreversible,featuring reduced expression of critical synaptic markers(PSD95,synaptophysin),impaired longterm potentiation(LTP),dendritic spine loss,and diminished neurotrophic support,especially brain-derived neurotrophic factor(BDNF)depletion,which collectively contribute to progressive cognitive decline and memory deficits.Mechanistic investigations identify three core pathways through which SD exerts its neurodegenerative effects:circadian rhythm disruption via BMAL1 suppression,orexin system hyperactivity leading to sustained wakefulness and metabolic stress,and oxidative stress accumulation through mitochondrial dysfunction and reactive oxygen species overproduction.The review critically evaluates promising therapeutic interventions including pharmacological approaches(melatonin,dual orexin receptor antagonists),metabolic strategies(ketogenic diets,and Mediterranean diets rich in omega-3 fatty acids),lifestyle modifications(targeted exercise regimens,cognitive behavioral therapy for insomnia),and emerging technologies(non-invasive photobiomodulation,transcranial magnetic stimulation).Current research limitations include insufficient understanding of dose-response relationships between SD duration/intensity and AD pathology progression,lack of long-term longitudinal clinical data in genetically vulnerable populations(particularly APOEε4 carriers and those with familial AD mutations),the absence of standardized SD protocols across experimental models that accurately mimic human chronic sleep restriction patterns,and limited investigation of sex differences in SDinduced AD risk.The accumulated evidence underscores the importance of addressing sleep disturbances as part of multimodal AD prevention strategies and highlights the urgent need for clinical trials evaluating sleep-focused interventions in at-risk populations.The review proposes future directions focused on translating mechanistic insights into precision medicine approaches,emphasizing the need for biomarkers to identify SD-vulnerable individuals,chronotherapeutic strategies aligned with circadian biology,and multi-omics integration across sleep,proteostasis and immune profiles may delineate precision-medicine strategies for at-risk populations.By systematically examining these critical connections,this analysis positions sleep quality optimization as a viable strategy for AD prevention and early intervention while providing a comprehensive roadmap for future mechanistic and interventional research in this rapidly evolving field.