Mechanisms of phototherapy of Alzheimer’s disease during sleep and wakefulness: the role of the meningeal lymphatics

Abstract

With the increase in the aging population, the global number of people with Alzheimer’s disease (AD) progressively increased worldwide. The situation is aggravated by the fact that there is no the effective pharmacological therapy of AD. Photobiomodulation (PBM) is non-pharmacological approach that has shown very promising results in the therapy of AD in pilot clinical and animal studies. However, the mechanisms of therapeutic effects of PBM for AD are poorly understood. In this study on mice, we demonstrate that photodynamic effects of 5-aminolevulenic acid and laser 635 nm cause reduction of network of the meningeal lymphatic vessels (MLVs) leading to suppression of lymphatic removal of beta-amyloid (Aβ) from the right lateral ventricle and the hippocampus. Using the original protocol of PBM under electroencephalographic monitoring of wakefulness and sleep stages in non-anesthetized mice, we discover that the 7-day course of PBM during deep sleep vs. wakefulness provides better restoration of clearance of Aβ from the ventricular system of the brain and the hippocampus. Our results shed light on the mechanism of PBM and show the stimulating effects of PBM on the brain lymphatic drainage that promotes transport of Aβ via the lymphatic pathway. The effects of PBM on the brain lymphatics in sleeping brain open a new niche in the study of restorative functions of sleep as well as it is an important informative platform for the development of innovative smart sleep technologies for the therapy of AD. Graphical Abstract

Technology of the photobiostimulation of the brain’s drainage system during sleep for improvement of learning and memory in male mice

“…Emerging evidence indicates the important roles of BDS in the resistant to neurocognitive disorders [ 8 , 9 , 14 , 63 – 68 ]. Indeed, dysfunction of MLVs results in less drainage of brain fluids to the cervical lymph nodes [ 8 , 11 , 12 , 19 , 28 , 41 , 42 ]. Such disruption of MLVs also results in cognitive impairment and behavioral alterations [ 8 ].…”

“…Once configured the instrument was operated autonomously, logging its operations to be monitored via Wi-Fi connection. Wakefulness, NREM and rapid eye movement (REM) sleep were defined as described in our previous studies, where we demonstrate the EEG patterns and spectrum characteristics of wakefulness, NREM and REM sleep in mice [ 14 , 42 ]. Sleep scoring in mice has been extensively discussed in literature.…”

“…PBM activates lymphatic pumping via regulation of contraction cycle of LVs and phase of relaxation of LVs by activation of the intracellular reactive oxygen species and production of nitric oxide (NO) [ 23 , 25 , 26 , 41 ]. It is assumed that PBM can also lead to angio- and lymphangiogenesis, which might be another mechanism responsible for PBM-mediated stimulation of BDS [ 42 ].…”