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

通过近红外光光生物调节改善脑血流量和减少阿尔茨海默病进展的睡眠依赖性机制

• 批准号: 10655017
• 负责人: DMITRY GERASHCHENKO
• 金额: $ 66.91万
• 依托单位: BOSTON VA RESEARCH INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-15 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10655017
• 关键词: APP-PS1; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Amyloid beta-Protein; Animals; Arteries; Astrocytes; Blood Vessels; Brain; Brain region; Cell Culture Techniques; Cerebral Ischemia; Cerebrovascular Circulation; Clinical Trials; Data; Dependence; Disease Progression; Elements; Endothelial Cells; Endothelium; Exposure to; Frequencies; Generations; Hippocampus; Ischemic Brain Injury; Knock-in; Knock-out; Light; Measures; Mediator; Memory; Metabolic; Metabolic Clearance Rate; Mus; NOS3 gene; Neurons; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type I; Pathology; Penetration; Performance; Phosphorylation; Phototherapy; Play; Process; Production; Property; Proteins; Publishing; Pulsatile Flow; REM Sleep; Relaxation; Role; Senile Plaques; Series; Sleep; System; Testing; Therapeutic Effect; Tissues; Transgenic Mice; Vasodilation; Wakefulness; absorption; awake; brain tissue; clinically significant; design; experimental study; glymphatic flow; glymphatic system; improved; interest; mouse model; multiphoton microscopy; neuroblastoma cell; non rapid eye movement; novel strategies; offspring; photobiomodulation; tau Proteins; translational study; vasomotion; virtual; wasting; APP-PS1; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Amyloid beta-Protein; Animals; Arteries; Astrocytes; Blood Vessels; Brain; Brain region; Cell Culture Techniques; Cerebral Ischemia; Cerebrovascular Circulation; Clinical Trials; Data; Dependence; Disease Progression; Elements; Endothelial Cells; Endothelium; Exposure to; Frequencies; Generations; Hippocampus; Ischemic Brain Injury; Knock-in; Knock-out; Light; Measures; Mediator; Memory; Metabolic; Metabolic Clearance Rate; Mus; NOS3 gene; Neurons; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type I; Pathology; Penetration; Performance; Phosphorylation; Phototherapy; Play; Process; Production; Property; Proteins; Publishing; Pulsatile Flow; REM Sleep; Relaxation; Role; Senile Plaques; Series; Sleep; System; Testing; Therapeutic Effect; Tissues; Transgenic Mice; Vasodilation; Wakefulness; absorption; awake; brain tissue; clinically significant; design; experimental study; glymphatic flow; glymphatic system; improved; interest; mouse model; multiphoton microscopy; neuroblastoma cell; non rapid eye movement; novel strategies; offspring; photobiomodulation; tau Proteins; translational study; vasomotion; virtual; wasting

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.

使用近红外（NIR）光是一种有希望的治疗方法 阿尔茨海默氏病（AD）。尽管对使用PBM治疗广告感兴趣，但目前的应用仍在 由于对大脑中NIR光动作的机制的理解不足而阻碍。 此外，由于其不足 渗透到脑组织中。我们假设治疗基础的关键机制 AD中NIR光的性质包括激活内皮一氧化氮合酶（ENOS） 大脑，内皮细胞产生一氧化氮（NO）的增加，血管症，血糖增加 淀粉样β载荷和TAU病理的流量和还原。此外，我们假设这些 NIR-II光（1000-1700 nm）的脉动可以显着增强机制 非比型眼运动（NREM）睡眠期间的频率。我们的具体目标旨在测试钥匙 该假设的要素。我们计划测试NIR轻型处理是最有效的 在NIR-II窗口和NREM睡眠期间（AIM 1），NIR光刺激的速率而不是它 持续时间确定AD中PBM治疗的效率（AIM 2），而ENOS是关键 AD中NIR光的热作用介质，而神经元一氧化氮合酶（NNOS）不是 （目标3）。这，我们提出了一系列旨在提高我们的理解的翻译研究 或NIR光在减少AD病理学以及识别NIR光传递方式中的作用 这是治疗广告最有效的。