Mechanisms of Transthyretin Inhibition of β-Amyloid AggregationIn Vitro

Abstract

Tissue-specific overexpression of the human systemic amyloid precursor transthyretin (TTR) ameliorates Alzheimer's disease (AD) phenotypes in APP23 mice. TTR-␤-amyloid (A␤) complexes have been isolated from APP23 and some human AD brains. We now show that substoichiometric concentrations of TTR tetramers suppress A␤ aggregation in vitro via an interaction between the thyroxine binding pocket of the TTR tetramer and A␤ residues 18 -21 (nuclear magnetic resonance and epitope mapping). The K D is micromolar, and the stoichiometry is Ͻ1 for the interaction (isothermal titration calorimetry). Similar experiments show that engineered monomeric TTR, the best inhibitor of A␤ fibril formation in vitro, did not bind A␤ monomers in liquid phase, suggesting that inhibition of fibrillogenesis is mediated by TTR tetramer binding to A␤ monomer and both tetramer and monomer binding of A␤ oligomers. The thousandfold greater concentration of tetramer relative to monomer in vivo makes it the likely suppressor of A␤ aggregation and disease in the APP23 mice.

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

“…However, results obtained by other authors suggest that it is the monomeric form of TTR that preferentially binds Aβ (20), especially when the peptide is in oligomeric form (21). The monomeric form of TTR was also shown to be the most efficient at inhibiting Aβ fibril formation, although by isotherm titration calorimetry (ITC), the monomeric TTR did not exhibit any sign of binding to Aβ, contrary to the tetramer (21). Also, it has been shown that Aβ oligomerrelated toxicity can be neutralized by the binding of TTR (especially monomeric TTR) by promoting their assembly into larger nontoxic species (22).…”

“…Importantly, in vivo administration of one such drug resulted in the amelioration of AD features (19). However, results obtained by other authors suggest that it is the monomeric form of TTR that preferentially binds Aβ (20), especially when the peptide is in oligomeric form (21). The monomeric form of TTR was also shown to be the most efficient at inhibiting Aβ fibril formation, although by isotherm titration calorimetry (ITC), the monomeric TTR did not exhibit any sign of binding to Aβ, contrary to the tetramer (21).…”

“…Although the results point to increased efficiency of the monomeric TTR, most of the data were obtained using an engineered TTR that exists as a stable monomer and whose existence in vivo has not been demonstrated. In fact, Li and colleagues suggest that in vivo, the inhibition of Aβ fibrillogenesis should be mediated by TTR tetramer binding to Aβ monomer; however, when oligomers are formed, tetrameric and monomeric TTR bind to Aβ oligomers, neutralizing its toxicity (21).…”

Transthyretin microheterogeneity and molecular interactions: implications for amyloid formation

“…Besides its transporter functions, TTR is implicated in a wide variety of additional physiological processes, such as thermoregulation and endocrine roles, and is produced at several sites. In addition, it has been shown to exert protease activity and chaperonelike actions (3,4), which may provide links between TTR and Alzheimer's disease (5,6).…”

Proteostatic Hotspots in Amyloid Fibrils Protect Us from Neurodegeneration

“…Indeed, the activity of Brichos is reminiscent of the ability of transthyretin (TTR), an abundant extracellular protein secreted from the liver and the choroid plexus, which has also been shown to reduce Ab aggregation (Li et al, 2013). Brichos and related amyloid chaperone managers belong to what we have defined as the ''outside'' proteostatic network (Powers and Balch, 2011).…”