The effectiveness of photobiomodulation of the brain and its meninges determined by age and the integrity of the lymphatic pathways of brain drainage and clearance

Photobiomodulation (PBM) is a promising therapeutic intervention for age-related neurodegenerative diseases. It has recently been discovered that the meningeal lymphatic vessels (MLVs) are targets for PBM, which mediates a PBM-related increase in brain drainage and clearance. However, with age, the MLV function significantly declines, which may impact the effectiveness of PBM for treating the aging brain. Age-related differences in sensitivity to PBM remain poorly understood, which motivated our research. The studies were conducted on C57BL/6 male mice at key age stages, including young (3 months), middle-aged (6 months), transitional (12 months), aging (18 months), and old (24 months) age, with a focus on examining the 10-day course of PBM (LED 1050[Formula: see text]nm in pulse mode, 30[Formula: see text]J/cm ² for one PBM exposure) effects on the lymphatic clearance of the toxic metabolite amyloid beta (A[Formula: see text]) from the brain assessed by ex vivo confocal analysis of intensity of fluorescent signal from A[Formula: see text] in the brain, its meninges and in the deep cervical lymph nodes as well as by immunohistochemical assay of A[Formula: see text]1–42 levels in the tested tissues. The results clearly demonstrate age-related changes in the MLV network and the effects of PBM on A[Formula: see text] clearance. Beginning at 12 months, a gradual proliferation of the MLV lymphatic endothelium was observed, with a dramatic decrease in A[Formula: see text] clearance in 18- and especially 24-month-old mice, suggesting that these changes lead to a decline in the MLV function of A[Formula: see text] removal from the brain with age. Indeed, we observed an increase in A[Formula: see text] levels in the brain and meninges in 18- and, most significantly, 24-month-old mice. PBM effectively reduces high A[Formula: see text] levels in the brain and meninges in 18-month-old mice to the level of 12-month-old mice, but no PBM effects are observed in 24-month-old mice. The obtained results highlight parallel processes that may be interrelated, i.e., aging of MLVs and the effectiveness of PBM stimulation of their function in the form of A[Formula: see text] clearance. These findings provide an important informative basis for improving the clinical guidance for PBM use for the treatment of brain diseases associated with amyloidosis and contribute to a better understanding of the limitations of PBM in elderly patients.