Synthesis and Structure-Function Analyses of the Toxic Dimer and Trimer Models of Amyloid β

Abstract

Accumulated evidences suggest that soluble oligomers of amyloid β42 and 40 (Aβ42 and 40) would be responsible for the Alzheimer’s disease. We proposed putative toxic dimer and trimer structures of Aβ42 with a turn at positions 22 and 23 (toxic turn) based on the systematic proline replacement, electron spin resonance, and solid-state NMR. Based on these structures, we synthesized several dimer models of the toxic-conformation-restricted E22P-Aβ40 using an ʟ,ʟ-2,6-diaminopimeric acid (DAP) or an ʟ,ʟ-2,8-diaminoazelaic acid linker (DAZ) at position 30 or 38 (Fig. 4, 1～3). The trimer models of E22P-Aβ40 using 1,3,5-phenyltris-ʟ-alanine (PtA) as a linker at position 34, 36, or 38 were also synthesized (Fig. 9, 4～6). Ion mobility-mass spectrometry suggested that high-molecular weight oligomers (12～24-mer) were formed only in the dimer model with DAP linker at position 38 (3), and this model exhibited potent neurotoxicity against SH-SY5Y cells. Although only the trimer model with PtA at position 38 (6) existed as high-molecular weight oligomers (9～21-mer), its neurotoxicity was far less than that of the corresponding dimer model (3). These data indicate that the C-terminal hydrophobic core plays an important role for the formation of high molecular weight oligomers (～20-mer) with neurotoxicity, and such a propeller-type trimer model (6) could not give oligomers with potent neurotoxicity. Similar results were obtained using the corresponding dimer and trimer models of E22P-Aβ42 (E22P-V40DAP-Aβ42 dimer, E22P-V36PtA-Aβ42 trimer, and E22P-V40PtA-Aβ42 trimer), suggesting that the results obtained in the Aβ40 dimer and timer models could be extended to the models of more toxic Aβ42.