Blokhina Inna

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.

The progressive number of old adults with cognitive impairment worldwide and the lack of effective pharmacologic therapies require the development of non-pharmacologic strategies. The photobiomodulation (PBM) is a promising method in prevention of early or mild age-related cognitive impairments. However, it remains unclear the efficacy of PBM for old patients with significant age-related cognitive dysfunction. In our study on male mice, we show a gradual increase in the brain amyloid beta (Aβ) levels and a decrease in brain drainage with age, which, however, is associated with a decline in cognitive function only in old (24 months of age) mice but not in middle-aged (12 months of age) and young (3 month of age) animals. These age-related features are accompanied by the development of hyperplasia of the meningeal lymphatic vessels (MLVs) in old mice underlying the decrease in brain drainage. PBM improves cognitive training exercises and Aβ clearance only in young and middle-aged mice, while old animals are not sensitive to PBM. These results clearly demonstrate that the PBM effects on cognitive function are correlated with age-mediated changes in the MLV network and may be effective if the MLV function is preserved. These findings expand fundamental knowledge about age differences in the effectiveness of PBM for improvement of cognitive functions and Aβ clearance as well as about the lymphatic mechanisms responsible for age decline in sensitivity to the therapeutic PBM effects.

Age is a limiting factor in the efficacy of photobiomodulation (PBM) for brain drainage and cognitive functions. Meningeal lymphatic vessels (MLVs) are "tunnels" for removal of toxins from the brain and the target of PBM. Age-related decline in the MLV functions is one of the mechanisms by which the effects of PBM on brain drainage and cognitive process are limited. Sleep is a time of natural activation of brain drainage. Recent findings have shown that PBM during sleep has greater effects on lymphatic clearance of beta-amyloid and cognitive function in young and middle-age mice. Based on these data, this study tested the hypothesis that sleep enhances the effects of PBM on MLVs and cognitive function in the aging brain. Indeed, the results revealed that PBM during sleep, but not during wakefulness, has stimulatory effects on lymphatic clearance of beta-amyloid from the brain of old mice that improves memory. In sleep deficit experiments, it was found that chronic sleep deprivation is accompanied by suppression of brain drainage and removal of metabolites from the brain, such as beta-amyloid, tau, glutamate, lactate and glucose in young, middle-aged and most significantly in old mice. The course of PBM during sleep contributed better than in wakefulness to the restoration of the brain level of tested metabolites in young and middle-aged mice, while in old mice only PBM during sleep was effective. These results open a new strategy for the use of PBM during sleep to improve the efficacy of PBM on clearance of toxic metabolites from the brain, especially in aged subjects in whom the efficacy of PBM during wakefulness is limited.