Transthyretin participates in beta-amyloid transport from the brain to the liver-involvement of the low-density lipoprotein receptor-related protein 1?

Transthyretin (TTR) binds A beta peptide, preventing its deposition and toxicity. TTR is decreased in Alzheimer's disease (AD) patients. Additionally, AD transgenic mice with only one copy of the TTR gene show increased brain and plasma A beta levels when compared to AD mice with both copies of the gene, suggesting TTR involvement in brain A beta efflux and/or peripheral clearance. Here we showed that TTR promotes A beta internalization and efflux in a human cerebral microvascular endothelial cell line, hCMEC/D3. TTR also stimulated brain-to-blood but not blood-to-brain A beta permeability in hCMEC/D3, suggesting that TTR interacts directly with A beta at the blood-brain-barrier. We also observed that TTR crosses the monolayer of cells only in the brain-to-blood direction, as confirmed by in vivo studies, suggesting that TTR can transport A beta from, but not into the brain. Furthermore, TTR increased A beta internalization by SAHep cells and by primary hepatocytes from TTR+/+ mice when compared to TTR-/- animals. We propose that TTR-mediated A beta clearance is through LRP1, as lower receptor expression was found in brains and livers of TTR-/- mice and in cells incubated without TTR. Our results suggest that TTR acts as a carrier of A beta at the blood-brain-barrier and liver, using LRP1.