Elucidating circuit disruptions in Alzheimer's disease

摘要 阿尔茨海默病(AD)是痴呆症的主要病因，目前尚无有效的治疗方法。一批 据报道，临床试验失败的原因是对阿尔茨海默病的病因缺乏完全的了解。 神经元活动障碍被描述为疾病的病因和 进步。慢波活动的异常，特别是慢振荡(振荡)对 据报道，阿尔茨海默氏症患者在NREM睡眠期间记忆巩固，可能有 导致了他们的痴呆症。然而，这种干扰的细胞机制尚不清楚。投稿 已经提出了神经元过度活动的可能性。目前尚不清楚大胶质细胞是否会导致过度活动和 慢波像差。因此，迫切需要了解大胶质细胞对神经元的影响。 活动中断，如慢波，以更好地了解AD的病因，并减轻其痴呆症负担。 我们将使用阿尔茨海默病的转基因小鼠模型来系统地评估大胶质细胞 使用多光子显微镜的钙成像技术有助于神经元活动中断。我们还将 利用光遗传学研究大胶质细胞是否在慢波活动中断中起因果作用。我们 假设大胶质细胞的作用大于神经元活动的动态平衡调节器。我们 建议利用光遗传学控制神经元回路，旨在恢复神经元的活动和减慢 阿尔茨海默氏症的进展。因此，我们的发现将决定细胞和分子之间的关系 神经元活性与阿尔茨海默病之间的关系，靶向大胶质细胞是一种新的治疗方法。

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.