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

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.