ABSTRACT
Transthyretin (TTR) binds Aß 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 Aß levels when compared to AD mice with both copies of the gene, suggesting TTR involvement in brain Aß efflux and/or peripheral clearance. Here we showed that TTR promotes Aß internalization and efflux in a human cerebral microvascular endothelial cell line, hCMEC/D3. TTR also stimulated brain-to-blood but not blood-to-brain Aß permeability in hCMEC/D3, suggesting that TTR interacts directly with Aß 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 Aß from, but not into the brain. Furthermore, TTR increased Aß internalization by SAHep cells and by primary hepatocytes from TTR+/+ mice when compared to TTR-/- animals. We propose that TTR-mediated Aß 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 Aß at the blood-brain-barrier and liver, using LRP1.
