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

总结 阿尔茨海默病（Alzheimer's disease，AD）是痴呆的主要病因。大脑回路功能障碍是记忆的基础 老年痴呆症患者的损伤。然而，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 疾病的病因及其进展的因素。睡眠依赖性脑节律的异常， 在深度NREM睡眠期间，缓慢的振荡对巩固记忆很重要， 老年痴呆症患者越来越多的证据表明，缓慢振荡的破坏不仅仅是 这种疾病的症状，但促进阿尔茨海默氏症的进展，并可能导致痴呆症。因此，我们认为， 有必要开发针对回路功能恢复的治疗策略，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。 基于干细胞的疗法有望治疗包括阿尔茨海默病在内的许多神经系统疾病。 由于抑制性音调的缺陷是缓慢振荡中断的基础，因此通过 移植抑制性中间神经元祖细胞可能会恢复电路功能并减缓阿尔茨海默氏症 进展因此，分离MGE衍生的中间神经元祖细胞并将其移植到动物中， 将进行淀粉样变性模型。我们将系统地评估干细胞治疗是否能恢复 慢波活动，减缓神经病理生理学和挽救睡眠以及记忆障碍。我们 建议采用最先进的方法，包括宽场和多光子显微镜监测 电路功能以及光遗传学以高时间精度控制神经元活动。因此，作为 这项工作的结果，我们将开发和评估干细胞治疗的疗效， 阿尔茨海默氏病在淀粉样变性小鼠模型中的应用，从而打开了将细胞疗法转化为 作为新型治疗方法的一部分，减缓患者的AD进展。

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.