Synthesis and characterization of the amyloid ß40 dimer model with a linker at position 30 adjacent to the intermolecular ß-sheet region.

ABSTRACT

Amyloid fibrils in senile plaque mainly consist of the 40-mer and 42-mer amyloid ß-proteins (Aß40 and Aß42). Although Aß42 plays more important role in the pathogenesis of Alzheimer's disease (AD), Aß40 could be involved in the progression of AD pathology because of its large amount. Recent studies revealed that variable sizes of Aß oligomers contributed to the neuronal death and cognitive dysfunction. However, how large oligomeric species are responsible for AD pathogenesis remains unclear. We previously proposed a toxic dimer model of Aß with turn structure at positions 22 and 23 using solid-state NMR and systematic proline replacement. Based on this model, we herein show the synthesis and biological activities of an E22P-Aß40 dimer at position 30, which was connected to l,l-2,6-diaminopimeric acid. The E22P-Aß40 dimer formed stable 6∼8-mer oligomers without amyloid fibrils, but was not neurotoxic on human neuroblastoma cells. On the other hand, E22P-Aß40 generated high molecular-weight oligomers into fibrils, and showed the neurotoxicity. These results suggest that such kind of Aß40 dimer with a parallel ß-sheet might not be pathological.