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-觉醒中断和认知障碍是阿尔茨海默病的普遍现象和致残特征 (AD) 患者表现出严重的睡眠障碍，包括非快速眼动 (NREM) 中断。 NREM 睡眠的一个主要恢复特征是，它也与正常的认知功能有关。慢波活动 (SWA) 最近的研究结果表明 SWA 生成受损之间存在因果关系。睡眠期间和 AD 发病机制包括淀粉样蛋白-β (Aβ) 肽的细胞外积累和虽然有证据表明皮质-丘脑环路调节 SWA，但确切的细胞功能障碍。 AD 中 SWA 受损的分子机制尚不清楚，因此需要对细胞进行表征。和负责 SWA 生成的分子机制，以减少 SWA 和我们提出的研究将阐明 SWA 的睡眠状态相关机制。使用 AD 动物模型进行的研究表明，抑制性神经传递受损。该提案的总体目标是确定和激励特定的 SWA。调节中间神经元以确定哪些细胞恢复 SWA 并使用在此，我们建议采用光遗传学和化学遗传学来控制AD小鼠模型。神经元回路旨在恢复 SWA 并减缓 AD 进展，因此，我们的研究结果将决定细胞。睡眠与 AD 之间的分子关系，以及特定时期的中间神经元的靶向睡眠作为一种新颖的治疗方法。

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）

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

阿尔茨海默病小鼠模型中兴奋性神经元活动减少和中间神经元类型特异性缺陷。

DOI：
发表时间：
2022-12-02
期刊：
影响因子：
5.9
作者：
Algamal, Moustafa;Russ, Alyssa N;Miller, Morgan R;Hou, Steven S;Maci, Megi;Munting, Leon P;Zhao, Qiuchen;Gerashchenko, Dmitry;Bacskai, Brian J;Kastanenka, Ksenia V
通讯作者：
Kastanenka, Ksenia V

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

通过光遗传学靶向 GABA 能神经元来恢复睡眠，可重新编程小胶质细胞并改善阿尔茨海默病模型中的病理表型。

DOI：
发表时间：
2023-12-01
期刊：
影响因子：
15.1
作者：
Zhao, Qiuchen;Maci, Megi;Miller, Morgan R;Zhou, Heng;Zhang, Fang;Algamal, Moustafa;Lee, Yee Fun;Hou, Steven S;Perle, Stephen J;Le, Hoang;Russ, Alyssa N;Lo, Eng H;Gerashchenko, Dmitry;Gomperts, Stephen N;Bacskai, Brian J;Kastanenka, Ksenia V
通讯作者：
Kastanenka, Ksenia V

Slow Wave Sleep Is a Promising Intervention Target for Alzheimer's Disease.

慢波睡眠是阿尔茨海默病的一个有前景的干预目标。

DOI：
发表时间：
2020
期刊：
影响因子：
0
作者：
Lee, Yee Fun;Gerashchenko, Dmitry;Timofeev, Igor;Bacskai, Brian J;Kastanenka, Ksenia V
通讯作者：
Kastanenka, Ksenia V

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

小鼠睡眠-觉醒周期实时分析的优化。

DOI：
发表时间：
2022
期刊：
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