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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease pathology Alzheimer&apos 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

项目摘要

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.

睡眠效果干扰和认知障碍是阿尔茨海默氏病的普遍性和致命特征（广告）。 AD患者表现出严重的睡眠障碍，包括破坏非比型眼运动（NREM）睡觉。 NREM睡眠的主要恢复特征，也与适当的认知功能有关，是慢波活动（SWA）。最近的发现表明SWA产生受损之间存在因果关系在睡眠和AD发病机理中，包括淀粉样蛋白β（Aβ）胡椒的细胞外积累和神经元功能障碍。虽然证据表明皮质 - 丘脑环调节SWA，但精确的细胞 AD中SWA受损的分子机制尚不清楚。那就是存在表征细胞的需求以及负责SWA产生的分子机制，以减少SWA的损伤和 AD发病机理。我们提出的研究将阐明SWA的睡眠状态相关机制防止AD。使用AD动物模型的研究表明，抑制性神经传递受到损害在SWA期间。该提案的总体目的是识别和刺激特定的SWA 调节神经元以确定哪些细胞恢复SWA并使用AD相关病理来减轻与AD相关的病理已建立的AD鼠标模型。在此，我们建议使用光遗传学和化学遗传学来控制神经元电路旨在恢复SWA并缓慢进展。那，我们的发现将决定细胞睡眠与AD之间的分子关系，在特定时期的靶向中间神经元的靶向作为一种新颖的治疗方法睡眠。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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
作者：
通讯作者：

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
作者：
通讯作者：

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Brian J Bacskai其他文献

Apolipoprotein E, especially apolipoprotein E4, increases the oligomerization of amyloid beta peptide. Gordon Research Conferences, Neurobiology of brain disorders

载脂蛋白E，尤其是载脂蛋白E4，增加淀粉样β肽的寡聚化。

DOI：
发表时间：
2012
期刊：
影响因子：
0
作者：
Tadafumi Hashimoto;Alberto Serrano-Pozo;Yukiko Hori;Hwan-Ching Tai;Kenneth W Adams;Shuko Takeda;Daniel Joyner;Diana H Thyssen;Brian J Bacskai;Matthew P Frosch;Tara L Spires-Jones;Mary Beth Finn;David M Holtzman;and Bradley T Hyman
通讯作者：
and Bradley T Hyman