Amyloid fibrils in senile plaque mainly consist of the 40-mer and 42-mer amyloid beta-proteins (A beta 40 and A beta 42). Although A beta 42 plays more important role in the pathogenesis of Alzheimer's disease (AD), A beta 40 could be involved in the progression of AD pathology because of its large amount. Recent studies revealed that variable sizes of A beta 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 A beta 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-A beta 40 dimer at position 30, which was connected to L,L-2,6-diaminopimeric acid. The E22P-A beta 40 dimer formed stable 6 similar to 8-mer oligomers without amyloid fibrils, but was not neurotoxic on human neuroblastoma cells. On the other hand, E22P-A beta 40 generated high molecular-weight oligomers into fibrils, and showed the neurotoxicity. These results suggest that such kind of A beta 40 dimer with a parallel beta-sheet might not be pathological. (C) 2015 Elsevier Inc. All rights reserved.