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

摘要 阿尔茨海默病(AD)是痴呆症的主要原因。大脑回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，临床试验中追求的治疗方法未能达到目标 直接接通线路。目前还没有治愈的方法。神经元活动中断被描述为 影响疾病病因及其进展的因素。睡眠依赖的大脑节律异常，特别是 在深度NREM睡眠中，缓慢振荡对巩固记忆非常重要，已在 阿尔茨海默氏症患者。越来越多的证据表明，慢振荡中的扰动并不是简单的 这是疾病的症状，但会促进阿尔茨海默氏症的进展，并可能导致痴呆症。因此， 有必要制定以恢复电路功能为目标的治疗策略，如慢波 活动，以恢复与睡眠依赖记忆功能障碍相关的认知损害。 基于干细胞的疗法有望治疗包括阿尔茨海默病在内的许多神经疾病。 由于抑制音的缺陷减慢了振荡的中断，抑制音通过 抑制性神经元间祖细胞移植可能恢复电路功能并延缓阿尔茨海默病 进步。因此，分离MGE来源的神经元间祖细胞并将其移植到动物体内 制作淀粉样变性模型。我们将系统地评估干细胞治疗是否能恢复 慢波活动，减缓神经病理生理，挽救睡眠和记忆障碍。我们 建议使用最先进的方法，包括广域和多光子显微镜来监测 电路功能以及光遗传学以高时间精确度控制神经元活动。因此，作为一个 这项工作的结果是，我们将开发和评估干细胞疗法治疗急性髓细胞白血病的疗效。 阿尔茨海默病在淀粉样变性小鼠模型中的作用，从而开启了将细胞治疗转化为 作为一种新的治疗方法的一部分，一种减缓患者阿尔茨海默病进展的疗法。

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.