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.

Learn about Alzheimer: The molecular conformation of a toxic β‐amyloid oligomer structure was determined by NMR spectroscopy (see picture). The measurements show a N‐terminal β strand that controls the partitioning between oligomer and protofibril formation. Targeting the N‐terminus of the peptide neutralizes Aβ‐dependent neuronal dysfunctions. The data have important implications for understanding the structural basis of Alzheimer's disease.

N-terminal truncation and pyroglutamyl (pE) formation are naturally occurring chemical modifications of the Aβ peptide in Alzheimer's disease. We show herein that these two modifications significantly reduce the fibril length and the transition midpoint of thermal unfolding of the fibrils, but they do not substantially perturb the fibrillary peptide conformation. This observation implies that the N terminus of the unmodified peptide protects Aβ fibrils against mechanical stress and fragmentation and explains the high propensity of pE-modified peptides to form small and particularly toxic aggregates.

Amyloid fibrils are linear polypeptide aggregates with a cross-β structure. These fibrils are best known for their association with neurodegenerative diseases, such as Alzheimer's or Parkinson's, but they may also be used by living organisms as functional units, e.g. in the synthesis of melanin or in the formation of bacterial biofilms. About a decade ago, in a search for semen factors that modulate infection by HIV-1 (a sexually transmitted virus and the causative agent of the acquired immune deficiency syndrome (AIDS)), it was demonstrated that semen harbors amyloid fibrils capable of markedly increasing HIV infection rates. This discovery not only created novel opportunities to prevent sexual HIV-1 transmission but also stimulated research to unravel the natural role of these factors. We discuss here the identification of these intriguing structures, their molecular properties, and their effects on both sexually transmitted diseases and reproductive health. Moreover, we review strategies to antagonize semen amyloid to prevent sexual transmission of viruses.