2D-L-1230 PDF
Measurements of toxic oligomers of amyloid β by ion mobility–mass spectrometry
The formation of soluble oligomers of amyloid β42 and 40 (Aβ42, Aβ40) is the initial event in the pathogenesis of Alzheimer's disease. We proposed a toxic dimer structure of Aβ42 with a turn at positions 22 and 23 based on the systematic proline replacement and solid-state NMR. Recently, we have synthesized several dimer models of the toxic-conformation-constrained E22P-Aβ40 and E22P-Aβ42 using L,L-2,6-diaminopimeric acid (DAP) or L,L-2,8-diaminoazelaic acid (DAZ) linker. E22P-A30DAP-Aβ40 dimer (1) and E22P-A30DAZ-Aβ40 dimer (2) existed mainly in oligomeric states even after 2 weeks incubation, but were not toxic against SH-SY5Y cells. In contrast, E22P-G38DAP-Aβ40 dimer (3) and E22P-V40DAP-Aβ42-dimer (4) exhibited potent neurotoxicity. Ion mobility–mass spectrometry suggested that 3 and 4 formed high molecular-weight oligomers (12 ~ 24-mer) after 4 hr incubation, but 1 and 2 did not. These findings indicate that the C-terminal hydrophobic core triggers the formation of toxic Aβ oligomers.