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

Abstract

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

Resveratrol Administration Increases Transthyretin Protein Levels, Ameliorating AD Features: The Importance of Transthyretin Tetrameric Stability

“…TTR is described as a transporter of T 4 and retinol; however, more recently it has been shown to be a binding partner for Aβ and suggested to be intimately involved in its clearance from the brain (17). As for resveratrol, apart from its potent antioxidant properties, several studies have demonstrated that this polyphenol also plays a neuroprotective role, although the mechanism by which this is performed is still unknown.…”

“…When TTR was genetically decreased, mice presented higher levels of Aβ (both Aβ 40 and Aβ 42 ) in the brain and plasma, accompanied by higher Aβ deposition (15,16) compared with control mice. This showed that TTR is an important molecule in the clearance of Aβ, with recent findings suggesting that TTR promotes Aβ efflux from the brain to the blood, possibly via LRP1 (17), although the exact mechanism is still unknown.…”

“…Primary hepatocytes were derived from nontransgenic TTR+/-mice, as previously described (17). Briefly, a cannula was inserted into the portal vein and perfusion medium (Hank's balanced salt solution [HBSS] 1 × medium containing 0.025 M HEPES and 2 mM ethylenediaminetetraacetic acid [EDTA]) was allowed to perfuse through the liver, with immediate cut of the vena cava.…”

Transthyretin—A Key Gene Involved in Regulating Learning and Memory in Brain, and Providing Neuroprotection in Alzheimer Disease via Neuronal Synthesis of Transthyretin Protein

“…TTR cleaves Aβ at multiple positions to degrade aggregated forms of Aβ. In vivo studies suggested that TTR can transport Aβ from the brain to blood but not into the brain [16]. TTR crosses the monolayer of cells only in the brain-to-blood direction.…”

“…TTR crosses the monolayer of cells only in the brain-to-blood direction. TTR-mediated Aβ clearance is through LRP1, as lower receptor expression was found in brains and livers of TTR knockdown mice and in cells incubated without TTR [16] [17]. The activated TTR may contribute not only to the upholding of Aβ levels within a normal range but also to the degradation of deposited Aβ in the case of imbalance and diseases condition [18].…”