Slow-wave activity as a modifier of the progression of neurodegeneration in Alzheimer's disease

慢波活动作为阿尔茨海默病神经变性进展的调节剂

• 批准号: 10205286
• 负责人: Brian J Bacskai
• 金额: $ 19.5万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-15 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10205286
• 关键词: Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease patient; Amyloid beta-Protein; Amyloid deposition; Animal Disease Models; Brain; Calcium; Cells; Cerebral cortex; Chronic; Data; Deposition; Disease Progression; Electroencephalogram; Electroencephalography; Enterobacteria phage P1 Cre recombinase; Exhibits; Generations; Glutamate Decarboxylase; Homeostasis; Impaired cognition; Impairment; Implant; Interneurons; Length; Light; Measures; Mediating; Memory; Molecular; Monitor; Mus; Nerve Degeneration; Neuronal Dysfunction; Neurons; Nitric Oxide Synthase Type I; Pathogenesis; Pathology; Pattern; Population; Production; Publications; Publishing; REM Sleep; Senile Plaques; Severities; Sleep; Sleep Architecture; Sleep disturbances; Somatostatin; Thalamic structure; Wakefulness; abeta accumulation; amyloid pathology; base; cell type; cognitive function; designer receptors exclusively activated by designer drugs; extracellular; improved; memory consolidation; mouse model; multiphoton microscopy; neuroinflammation; neuronal circuitry; neurotransmission; non rapid eye movement; novel therapeutic intervention; optical fiber; optogenetics; sleep pattern; voltage sensitive dye

Sleep-wake disruptions and cognitive impairments are prevalent and disabling features of Alzheimer's disease (AD). AD patients exhibit profound sleep disturbances including disruption of non-rapid eye movement (NREM) sleep. A major restorative feature of NREM sleep, which is also associated with proper cognitive functioning, is slow-wave activity (SWA). Recent findings suggest a causal relationship between impaired generation of SWA during sleep and AD pathogenesis including extracellular accumulation of the amyloid-β (Aβ) peptide and neuronal dysfunction. While evidence indicates that cortical-thalamic loops regulate SWA, the exact cellular and molecular mechanisms for impaired SWA in AD are unknown. Thus, a need exists to characterize the cells and molecular mechanisms responsible for SWA generation to reduce the impairments in SWA and pathogenesis of AD. We propose studies that will elucidate the sleep state related mechanisms by which SWA protects against AD. Studies using AD animal models suggest that inhibitory neurotransmission is impaired during periods of SWA. The overall objective of this proposal is to identify and stimulate specific SWA modulating interneuronals to determine which cells restore SWA and mitigate AD-related pathology using an established AD mouse model. Herein, we propose to employ optogenetics and chemogenetics to control neuronal circuits aimed to restore SWA and slow AD progression. Thus, our findings will determine the cellular and molecular relationships between sleep and AD, with the targeting of interneurons during specific periods of sleep as a novel therapeutic approach.

睡眠-觉醒中断和认知障碍是阿尔茨海默病的普遍和致残特征 （AD）。AD患者表现出严重的睡眠障碍，包括非快速眼动（NREM）中断 睡吧NREM睡眠的一个主要恢复特征，也与适当的认知功能有关， 慢波活动（SWA）。最近的研究结果表明SWA的产生受损之间存在因果关系 在睡眠和AD发病机制，包括细胞外积累的淀粉样β（Aβ）肽， 神经元功能障碍虽然有证据表明，皮质-丘脑回路调节SWA，但确切的细胞调节机制是， AD中SWA受损的分子机制尚不清楚。因此，需要表征细胞 以及负责SWA产生的分子机制，以减少SWA中的损伤， AD的发病机制我们提出的研究将阐明睡眠状态相关的机制，其中SWA 保护AD。使用AD动物模型的研究表明，抑制性神经传递受损 在SWA期间。本提案的总体目标是确定和激励具体的SWA 调节神经元间，以确定哪些细胞恢复SWA并减轻AD相关的病理， 建立AD小鼠模型。在此，我们建议采用光遗传学和化学遗传学来控制， 神经元回路旨在恢复SWA和减缓AD进展。因此，我们的研究结果将确定细胞 以及睡眠和AD之间的分子关系，在特定的睡眠期间靶向中间神经元。 睡眠作为一种新的治疗方法。

项目成果

Sleep restoration by optogenetic targeting of GABAergic neurons reprograms microglia and ameliorates pathological phenotypes in an Alzheimer's disease model.

• DOI: 10.1186/s13024-023-00682-9
• 发表时间: 2023-12-01
• 期刊: Molecular neurodegeneration
• 影响因子: 15.1

Optimization of real-time analysis of sleep-wake cycle in mice.

• DOI: 10.1016/j.mex.2022.101811
• 发表时间: 2022
• 期刊: METHODSX
• 影响因子: 1.9
• 作者: Thankachan, Stephen;Gerashchenko, Andrei;Kastanenka, Ksenia, V;Bacskai, Brian J.;Gerashchenko, Dmitry
• 通讯作者: Gerashchenko, Dmitry

Reduced excitatory neuron activity and interneuron-type-specific deficits in a mouse model of Alzheimer's disease.

• DOI: 10.1038/s42003-022-04268-x
• 发表时间: 2022-12-02
• 期刊: Communications biology
• 影响因子: 5.9