Sleep-dependent mechanisms of improving cerebral blood flow and reducing Alzheimer's disease progression by photobiomodulation with near-infrared light

利用近红外光进行脑光生物调节是一种很有前途的治疗新方法 阿尔茨海默病(AD)。尽管人们对使用PBM治疗AD非常感兴趣，但它的应用目前 由于对近红外光在大脑中的作用机制了解不足而受到阻碍。 此外，近红外I光(650-900 nm)由于其不足而没有达到临床意义 穿透到脑组织。我们假设治疗的关键机制 阿尔茨海默病的近红外光特性包括激活内皮型一氧化氮合酶(ENOS) 脑，内皮细胞产生一氧化氮(NO)增加，血管运动，淋巴增加 血流，淀粉样蛋白β负荷减少和tau病理。此外，我们假设这些 机制可以显著增强脉动的近红外-II光(1000-1700 nm)在低 非快速眼动(NREM)睡眠期间的频率。我们的具体目标是为了测试关键 这一假说的要素。我们计划测试近红外光治疗在交付时是最有效的 在NIR-II窗口和NREM睡眠期间(目标1)，近红外光刺激率而不是其 持续时间决定了阿尔茨海默病PBM治疗的效率(目标2)，eNOS是关键 近红外光治疗阿尔茨海默病的介体，而神经元型一氧化氮合酶不是 (目标3)。因此，我们提出了一系列的翻译研究，旨在提高我们的理解 或近红外光在减轻AD病理以及识别近红外光传递方式中的作用 这是治疗AD最有效的方法。

Brain photobiomodulation (PBM) using near-infrared (NIR) light is a promising new approach for treating Alzheimer’s disease (AD). Despite the high interest in using PBM to treat AD, its application is currently hindered by the insufficient understanding of the mechanisms of NIR light actions in the brain. Additionally, NIR-I light (650-900 nm) has not achieved clinical significance due to its insufficient penetration into the brain tissue. We hypothesize that the key mechanisms underlying treatment properties of NIR light in AD include the activation of endothelial nitric oxide synthase (eNOS) in the brain, increase of nitric oxide (NO) production by endothelial cells, vasomotion, increase of glymphatic flow, and reduction of amyloid β load and tau pathology. Further, we hypothesize that these mechanisms can be markedly enhanced by the pulsation of NIR-II light (1000-1700 nm) at a low frequency during non-rapid eye movement (NREM) sleep. Our specific aims are designed to test the key elements of this hypothesis. We plan to test that NIR light treatment is most efficient when it is delivered in NIR-II window and during NREM sleep (aim 1), that the rate of NIR light stimulation rather than its duration determines the efficiency of the PBM treatment in AD (aim 2), and that eNOS is the key mediator of therapeutic effects of NIR light in AD, whereas neuronal nitric oxide synthase (nNOS) is not (aim 3). Thus, we propose a series of translational studies that are aimed to improve our understanding or the role of NIR light in reducing the AD pathology as well as to identify the way of NIR light delivery that is most efficient in treating AD.