The presence of TTR in brain areas other than its site of synthesis and secretion – the choroid plexus (CP) and CSF, respectively–in situations of injury, such as ischemia, has been shown using a mouse model with compromised heat-shock response 12.
Growing evidence also suggests a wider role for TTR in CNS neuroprotection, including in ischemia 12, regeneration 13 and memory 14. Ribeiro and colleagues reported increased Aβ levels in both brain and plasma of AD mice with only one copy of the TTR gene, when compared to animals with two copies of the gene 11, suggesting a role for TTR in Aβ clearance. Evidence coming from in vivo studies in AD transgenic mice established in different TTR genetic backgrounds 9, 10 also suggests that TTR prevents Aβ deposition and protects against neurodegeneration, although the exact mechanism is still unknown. Data showing that TTR is decreased in both CSF 6 and plasma 7, 8 of AD patients, strengthen the idea of neuroprotection by TTR. These authors described that TTR was able to inhibit Aβ aggregation and toxicity, suggesting that when TTR fails to sequester Aβ, amyloid formation occurs 4, 5. Transthyretin (TTR), a 55 kDa homotetrameric protein involved in the transport of thyroid hormones and retinol, has been proposed as a protective protein in AD in the mid-nineties, when Schwarzman and colleagues described this protein as the major Aβ binding protein in CSF. With increasing age, the expression of the Aβ efflux transporters is decreased and the Aβ influx transporter expression is increased at the BBB, adding to the amyloid burden in the brain. While LRP1 appears to mediate the efflux of Aβ from the brain to the periphery, RAGE has been strongly implicated in Aβ influx back into the central nervous system (CNS). Both LRP1 and RAGE are multi-ligand cell surface receptors that, in addition to Aβ, mediate the clearance of a large number of proteins. The low-density lipoprotein receptor-related protein 1 (LRP1) and the receptor for advanced glycation end products (RAGE) are involved in receptor-mediated flux of Aβ across the BBB 3. The receptors for Aβ at the BBB bind Aβ directly, or bind to one of its carrier proteins and transport it across the endothelial cell.
Aβ peptide is generated upon sequential cleavage of the amyloid precursor protein (APP), by beta- and gamma-secretases and it is believed that an imbalance between Aβ production and clearance results in its accumulation in the brain.Ĭlearance of Aβ from the brain occurs via active transport at the blood-brain-barrier (BBB) and blood cerebrospinal fluid (CSF) barrier (BCSFB), in addition to the peptidolytic removal of the peptide by several enzymes. Pathologically, the disease is characterized by the presence of extraneuronal amyloid plaques consisting of aggregates of amyloid-beta (Aβ) peptide and neurofibrillary tangles (NFTs) which are intracellular aggregates of abnormally hyperphosphorylated tau protein 2. Our results suggest that TTR acts as a carrier of Aβ at the blood-brain-barrier and liver, using LRP1.Īlzheimer’s disease (AD), described for the first time by Alois Alzheimer in 1906, is characterized by progressive loss of cognitive functions ultimately leading to death 1. 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. Furthermore, TTR increased Aβ internalization by SAHep cells and by primary hepatocytes from TTR+/+ mice when compared to TTR−/− animals. 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. 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. Here we showed that TTR promotes Aβ internalization and efflux in a human cerebral microvascular endothelial cell line, hCMEC/D3. 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. TTR is decreased in Alzheimer’s disease (AD) patients. Transthyretin (TTR) binds Aβ peptide, preventing its deposition and toxicity.
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