. RAGE mediates amyloid-beta peptide transport across the blood-brain barrier and accumulation in brain. Nat Med. 2003 Jul;9(7):907-13. PubMed.

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  1. Data from several groups has suggested that the Ab peptide can be transported from the brain to the blood and from the blood to the brain to a greater extent than would be expected unless there were specific transporters for Ab at the blood-brain barrier. Several molecules have been previously implicated in this process. In this current work, Deane et al. examine the potential contribution of the molecule known as RAGE in the transport of Ab from the blood into the brain. Using sophisticated techniques and specific reagents, they show that when radiolabeled Ab is injected into the blood, its transport into brain (as reflected by the PS value or permeability surface area product) is consistent with it entering brain via a transporter. Further, RAGE appears to be required for this transport, at least at the doses of Ab utilized. These doses are much higher than are present in human plasma, but are similar to those found in some AbPP transgenic mice, such as Tg2676. In addition, it was shown that when a RAGE inhibitor (soluble RAGE) was administered to one type of AbPP transgenic mice that develop AD-like pathology, 1) plasma Ab increased more than 10-fold, and 2) over three months, there was a significant decrease in Ab load and levels.
    Other data presented suggest that Ab in blood, at doses injected, results in RAGE-mediated endothelial stress and decreased blood flow. The authors show that the PS value of soluble RAGE is very low and conclude that soluble RAGE exerts its effects in the periphery, and not via crossing the BBB.

    Taken together, these findings suggest that transport of Ab from blood to brain via RAGE may be playing a role in the development of Ab deposition in the brain. These are elegant studies, and the authors should be complimented for this work. In addition to the important implications for the involvement of RAGE with Ab transport, these studies highlight the critical need to further investigate the emerging field of Ab metabolism. A detailed understanding of the complex milieu of Ab anabolism/catabolism, and the influence therein of endogenous binding proteins and transporters, will be essential for future rationale-based therapeutics, as well as for the interpretation of biomarkers that are representative of altered pathological states.

    Further experiments to validate the role of RAGE in endogenous Ab metabolism would be to cross different lines of AbPP transgenic mice with RAGE knockout mice and to study not only time and amount of Ab deposition, but also the levels of endogenous Ab in brain and blood, as well as Ab metabolism. Utilizing lines of AbPP mice that have greater or lesser amounts of plasma Ab would assist in determining the role of RAGE in blood-to-brain transport of total brain Ab metabolism. This work suggests that further studies should be done to pursue the mechanisms by which endogenous Ab is transported both into and out of the brain. Also, the data further support that a "peripheral Ab sink" should continue to be explored as a basis for therapy.