Elucidating circuit disruptions in Alzheimer's disease

总结 阿尔茨海默病（Alzheimer's disease，AD）是痴呆症的主要病因，目前尚无有效的治疗方法.一些 临床试验失败的报道是由于缺乏对阿尔茨海默病病因的完全理解。 神经元活动中断已被描述为疾病病因学的促成因素， 进展慢波活动的异常，特别是慢振荡（振荡<1Hz），对 在NREM睡眠期间巩固记忆，已经在阿尔茨海默氏症患者中报道， 导致了他们的痴呆然而，这种破坏的细胞机制尚不清楚。贡献 神经元过度活跃的证据目前尚不清楚大胶质细胞是否有助于多动症， 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病因和减轻其痴呆负担。 我们将使用阿尔茨海默病的转基因小鼠模型系统地评估大胶质细胞是否 有助于使用钙成像与多光子显微镜的神经元活动中断。我们还将 使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 假设大胶质细胞所起作用大于神经元活动的稳态调节器。我们 我建议采用光遗传学来控制神经元回路，旨在恢复神经元活动， 阿尔茨海默病进展。因此，我们的研究结果将确定细胞和分子的关系， 神经元活动和AD之间的关系，靶向大胶质细胞作为一种新的治疗方法。

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.