Melatonin treatment enhances Aβ lymphatic clearance in a transgenic mouse model of amyloidosis.

Background: It has been postulated that inadequate clearance of the amyloid (beta protein (A beta) plays an important role in the accumulation of A beta in sporadic late onset Alzheimer's disease (AD). While the blood bram barrier (BBB) has taken the center stage in processes involving A beta clearance, little information is available about the role of the lymphatic system. We previously reported that A beta is cleared through the lymphatic system. We now assessed lymphatic A beta clearance by treating a mouse model of AD amyloidosis with melatonin, an A beta aggregation inhibitor and immuno-regulatory neurohormone. Objective: To confirm and expand our initial finding that A beta is cleared through the lymphatic system. Lymphatic clearance of metabolic and cellular "waste" products from the bram into the peripheral lymphatic system has been known for a long time. However, except for our prior report, there is no additional experimental data published about A beta being cleared into peripheral lymph nodes. Methods: For these experiments, we used a transgenic mouse model (Tg2576) that over-expresses a mutant form of the A beta precursor protein (APP) in the bram. We examined levels of A beta in plasma and in lymph nodes of transgenic mice as surrogate markers of vascular and lymphatic clearance, respectively. A beta levels were also measured in the bram and in multiple tissues. Results: Clearance of A beta peptides through the lymphatic system was confirmed in this study. Treatment with melatonin led to the following changes: 1-A statistically significant increase in soluble monomeric A beta 40 and an increasing trend in A beta 42 in cervical and axillary lymph nodes of treated mice. 2-Statistically significant decreases in oligomeric A beta 40 and a decreasing trend A beta 42 in the bram. Conclusion: The data expands on our prior report that the lymphatic system participates in A beta clearance from the bram. We propose that abnormalities in A beta clearance through the lymphatic system may contribute to the development of cerebral amyloidosis. Melatonin and related indole molecules (i e, indole-3-propionic acid) are known to inhibit A beta aggregation although they do not reverse aggregated A beta or amyloid fibrils. Therefore, these substances should be further explored in prevention trials for delaying the onset of cognitive impairment in high risk populations.