Elucidating circuit disruptions in Alzheimer's disease

阐明阿尔茨海默病的电路中断

• 批准号: 10055533
• 负责人: Ksenia V. Kastanenka
• 金额: $ 57.44万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10055533
• 关键词: Adopted; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease patient; Amyloidosis; Astrocytes; Autopsy; Brain; Calcium; Cells; Chronic; Clinical Trials; Cognitive; Coupling; Data; Dementia; Deposition; Development; Disease; Disease Progression; Electrodes; Electrophysiology (science); Elements; Etiology; Exhibits; Failure; Fourier Transform; Functional disorder; Glutamate-Ammonia Ligase; Glutamates; Glutaminase; Glutamine; Goals; Health; High Pressure Liquid Chromatography; Homeostasis; Hyperactive behavior; Image; Impaired cognition; Individual; Lead; Memory impairment; Metabolic; Molecular; Mus; Neurodegenerative Disorders; Neuroglia; Neurons; Neurosciences; Pattern; Play; Population; Process; Proteins; Regulation; Reporting; Rodent; Rodent Diseases; Role; Senile Plaques; Sleep; Testing; Therapeutic; Transgenic Mice; Work; behavior measurement; brain tissue; gamma-Aminobutyric Acid; in vivo calcium imaging; interest; macroglia; memory consolidation; molecular marker; mouse model; multiphoton microscopy; network dysfunction; neuronal circuitry; neuropathology; neurotransmission; non rapid eye movement; novel; novel therapeutic intervention; optogenetics; restoration; therapeutic development; tool; voltage sensitive dye

Summary Alzheimer’s disease (AD) is the major cause of dementia currently without an effective cure. A number of clinical trial failures has been reported due to a lack of complete understanding of Alzheimer’s disease etiology. Neuronal activity disruptions have been described as contributing factors to the disease etiology and its progression. Anomalies in slow wave activity, specifically slow oscillations (oscillations <1Hz) important for consolidation of memories during NREM sleep, have been reported in Alzheimer’s patients and might have contributed to their dementia. The cellular mechanisms of such disruptions however are unclear. Contributions of neuronal hyperactivity have been suggested. It is unknown whether macroglia contribute to hyperactivity and slow wave aberrations. Thus, there is an urgent need to understand the impact of macroglia on neuronal activity disruptions, such as slow waves, to better understand AD etiology and to alleviate its dementia burden. We will use transgenic mouse models of Alzheimer’s disease to systematically assess whether macroglia contributes to neuronal activity disruptions using calcium imaging with multiphoton microscopy. We will also investigate whether macroglia play a causal role in disruption of slow wave activity using optogenetics. We hypothesize that macroglia play a role greater than that of a homeostatic regulator of neuronal activity. We propose to employ optogenetics to control neuronal circuits aimed to restore neuronal activity and slow Alzheimer’s disease progression. Thus, our findings will determine the cellular and molecular relationships between neuronal activity and AD, with the targeting of macroglia as a novel therapeutic approach.

概括 阿尔茨海默氏病（AD）是目前没有有效治愈的痴呆症的主要原因。许多 据报道，由于对阿尔茨海默氏病病因的完全了解，临床试验失败。 神经元活性中断被描述为疾病病因及其ITS的促成因素 进展。慢波活动中的异常，特别是缓慢振荡（振荡<1Hz） NREM睡眠期间的记忆巩固已经报道了阿尔茨海默氏症患者，可能有 为他们的痴呆症做出了贡献。但是，这种干扰的细胞机制尚不清楚。贡献 已经提出了神经元多动症。尚不清楚大胶体是否有助于多动症和 慢波像差。这是迫切需要了解大元对神经元的影响 活动中断，例如慢波，以更好地理解AD病因并减轻其痴呆症负担。 我们将使用阿尔茨海默氏病的转基因小鼠模型系统地评估大元是否是否 使用多光子显微镜钙成像促进神经元活性破坏。我们也会 研究大胶质细胞在使用光遗传学破坏慢波活性中是否起因果作用。我们 假设大胶质细胞的作用大于神经元活性的稳态调节剂的作用。我们 向员工光遗传学的提议控制旨在恢复神经元活动和缓慢的神经元电路 阿尔茨海默氏病进展。这是我们的发现将决定细胞和分子关系 在神经元活性和AD之间，将大胶质细胞作为一种新的治疗方法。