Stockholm. A growing line of investigation in Alzheimer’s research suggests that the Aβ peptide produced in the brain is transported into the periphery on a routine basis, and that this transport chain, whatever its precise mechanism, could perhaps be exploited for therapy one day by “drawing” Aβ out of the brain. One simple but unanswered question here is what happens to peripheral, circulating Aβ. This is important to know not just for future therapeutic applications but also for a better understanding of how Aβ gets turned over during a person’s many decades of healthy life prior to the onset of AD. How does the body dispose of it normally, and why is it accumulating only in the brain, not in the periphery?

On Monday, Miguel Calero, working with Jorge Ghiso and others at New York University School of Medicine, presented a poster here at the 8th International Conference on Alzheimer’s Disease and Related Disorders that revealed some of the pharmacokinetics of soluble Aβ40 and 42. Calero et al. radiolabeled Aβ with a sugar that allows cells to take up circulating serum Aβ into their lysosomes but then traps it there because the lysosomes cannot degrade the sugar. They injected this once into the tail vein of mice and checked which organs had taken up most of the Aβ at several time points up to 10 hours later.

The researchers found that the liver accounted for 60 percent of the total peptide uptake (followed by the kidney), with 87 percent of that stuck in hepatocytes, not other cell types in the liver. Some labeling was in the gall bladder and small intestine, suggesting that it is being excreted via bile. This finding fuels the--largely speculative-notion that Aβ buildup in the LOAD brain could, at least in part, result from a problem in the liver, essentially causing a backup at the source as transport and peripheral clearance gradually fail due to age-related decline.—Gabrielle Strobel


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