Development and evaluation of cell therapy strategies for Alzheimer's disease.

阿尔茨海默病细胞治疗策略的开发和评估。

• 批准号: 10524288
• 负责人: Ksenia V. Kastanenka
• 金额: $ 44.57万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10524288
• 关键词: APP-PS1; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Amyloid beta-Protein; Amyloid deposition; Amyloidosis; Animal Model; Automobile Driving; Behavior assessment; Brain; Calcium; Cell Death; Cell Survival; Cell Therapy; Cell Transplantation; Clinical Trials; Cognition; Data; Dementia; Deposition; Development; Disease; Disease Progression; Embryonic Stem Cell Transplantation; Etiology; Evaluation; Exhibits; Frequencies; Functional disorder; GABA Receptor; Ganglia; Harvest; Health; Homeostasis; Impaired cognition; Impairment; Interneurons; Medial; Memory; Memory impairment; Methodology; Monitor; Mus; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Patients; Positioning Attribute; Property; Publishing; Recovery; Reporting; Research; Senile Plaques; Sleep; Testing; Thalamic structure; Therapeutic; Time; Translating; Transplantation; Work; behavior measurement; efficacy evaluation; embryonic stem cell; experience; extracellular; falls; fetal; in vivo calcium imaging; innovation; memory consolidation; mouse model; multiphoton microscopy; neocortical; nervous system disorder; neuron loss; neuronal circuitry; non rapid eye movement; novel; novel therapeutic intervention; optogenetics; preservation; progenitor; programs; restoration; sensor; stem cell therapy; stem cells; voltage

Summary Alzheimer’s disease (AD) is the major cause of dementia. Brain circuit dysfunctions underlie the memory impairments of Alzheimer’s patients. Yet therapeutic approaches pursued in clinical trials failed to target circuits directly. Currently there is no cure. Neuronal activity disruptions have been described as contributing factors to the disease etiology and its progression. Anomalies in sleep-dependent brain rhythms, specifically slow oscillations important for consolidation of memories during deep NREM sleep, have been reported in Alzheimer’s patients. Converging evidence suggests that disruptions in slow oscillations are not simply symptomatic of the disease but facilitate Alzheimer’s progression and might contribute to dementia. Therefore, it is necessary to develop therapeutic strategies targeting restoration of circuit function, such as slow wave activity, to restore cognitive impairments associated with sleep-dependent memory dysfunction. Stem cell-based therapies hold promise for a number of neurological disorders including Alzheimer’s disease. Since deficits in inhibitory tone underly slow oscillation disruptions, restoration of inhibitory tone through transplantation of inhibitory interneuron progenitors might restore circuit function and slow Alzheimer’s progression. Thus, isolation of MGE-derived interneuron progenitors and their transplantation into an animal model of amyloidosis will be performed. We will systematically evaluate whether stem cell therapy restores slow wave activity, slows neuropathophysiology and rescues sleep as well as memory impairments. We propose to employ state-of-the-art methodology including widefield and multiphoton microscopy to monitor circuit function as well as optogenetics to control neuronal activity with high temporal precision. Thus, as a result of this work we will develop and evaluate the efficacy of stem cell therapy for the treatment of Alzheimer’s disease in a mouse model of amyloidosis, thus opening the possibility of translating cell therapy as a cure to slow AD progression in patients as part of a novel therapeutic approach.

概括 阿尔茨海默氏病（AD）是痴呆症的主要原因。脑电路功能障碍是记忆的基础 阿尔茨海默氏症患者的损害。然而，在临床试验中采用的治疗方法未能针对 电路直接。目前没有治愈方法。神经元活动中断被描述为贡献 疾病病因及其进展的因素。睡眠依赖性脑节律中的异常，特别是 据报道，缓慢的振荡对于在深度NREM睡眠期间的记忆巩固很重要 阿尔茨海默氏症患者。融合证据表明，缓慢振荡的中断不仅仅是 这种疾病的症状，但促进了阿尔茨海默氏症的进展，可能会导致痴呆症。所以， 有必要制定针对恢复电路功能的理论策略，例如慢波 活动，以恢复与睡眠依赖性记忆功能障碍相关的认知障碍。 基于干细胞的疗法对包括阿尔茨海默氏病在内的多种神经系统疾病有望。 由于定义了抑制性语调的基础较慢的振荡破坏，因此通过 抑制性中间神经元祖细胞的移植可能会恢复电路功能并减慢阿尔茨海默氏症的速度 进展。那是MGE衍生的中间祖细胞的隔离及其移植到动物 将进行淀粉样变性的模型。我们将系统地评估干细胞疗法是否恢复 慢波活动，减慢神经病理生理学并营救睡眠以及记忆障碍。我们 提出采用最先进方法的提案，包括广场和多光子显微镜监测 电路功能以及光遗传学以高临时精度控制神经元活动。那是一个 这项工作的结果我们将开发和评估干细胞疗法的治疗效率 阿尔茨海默氏病在小鼠淀粉样变性的小鼠模型中，因此开放了将细胞疗法转化为 作为一种新型治疗方法的一部分，可以减慢患者的AD进展。