Background: It has been postulated that inadequate clearance of the amyloid β protein (Aβ)
plays an important role in the accumulation of Aβ in sporadic late onset Alzheimer's disease (AD).
While the blood brain barrier (BBB) has taken the center stage in processes involving Aβ clearance, little
information is available about the role of the lymphatic system. We previously reported that Aβ is
cleared through the lymphatic system. We now assessed lymphatic Aβ clearance by treating a mouse
model of AD amyloidosis with melatonin, an Aβ aggregation inhibitor and immuno-regulatory neurohormone.
Objective: To confirm and expand our initial finding that Aβ is cleared through the lymphatic system.
Lymphatic clearance of metabolic and cellular “waste” products from the brain 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 Aβ 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 Aβ precursor protein (APP) in the brain. We examined levels of Aβ in plasma and in
lymph nodes of transgenic mice as surrogate markers of vascular and lymphatic clearance, respectively.
Aβ levels were also measured in the brain and in multiple tissues.
Results: Clearance of Aβ 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
Aβ40 and an increasing trend in Aβ42 in cervical and axillary lymph nodes of treated mice. 2-
Statistically significant decreases in oligomeric Aβ40 and a decreasing trend Aβ42 in the brain.
Conclusion: The data expands on our prior report that the lymphatic system participates in Aβ clearance
from the brain. We propose that abnormalities in Aβ 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 Aβ aggregation although they do not reverse aggregated Aβ or
amyloid fibrils. Therefore, these substances should be further explored in prevention trials for delaying
the onset of cognitive impairment in high risk populations.