Synthesis of chemically-tethered amyloid-β segment trimer possessing amyloidogenic properties

As amyloid-beta (A beta) undergoes dynamic aggregation, it is impossible to isolate ('hook') the transient A beta oligomer in an assembly state-pure form (e.g., sole A beta dimer, trimer, tetramer, etc.). Obtaining such a pure A beta oligomer would allow us to establish an in vitro system to perform a more detailed investigation of the pathogenic properties of the oligomer. A chemically-tethered A beta oligomer, constructed only by covalent bonds, could satisfy this demand. Here we designed a chemically-tethered trimer of a pathogenic A beta fragment (A beta(25-35)) (1) and successfully generated it in situ from its precursor (4), a water-soluble and nonaggregative O-acyl isopeptide of 1, in neutral aqueous media. Chemically-tethered 1 possessed stronger amyloidogenic properties, that is, potential for beta-sheet structure, fibril formation, and cytotoxicity, than the corresponding monomer A beta(25-35) (6). Trimerization of A beta(25-35) sequence might affect both the aggregative properties and cytotoxicity, based on the present results. This work opens the door for chemical synthesis of oligomers bigger than trimers in an assembly state-pure form, allowing for identification of the most toxic A beta oligomer. (C) 2015 Published by Elsevier Ltd.