Membrane-bound tetramer and trimer Aβ oligomeric species correlate with toxicity towards cultured neurons

Amyloid beta (Ab) peptide is the major constituent of the extracellular amyloid plaques deposited in the brains of Alzheimer's disease patients and is central to the pathogenic pathway causing this disease. The identity of the neurotoxic Ab species remains elusive. We previously reported that Ab toxicity correlates strongly with its neuronal cell binding leading us to hypothesize that neuronal cell death is caused by the binding of a specific oligomeric Ab species. To identify the specific oligomeric Ab species that is associated with cell death, we treated mouse cortical neuronal cultures with synthetic A beta 40 and A beta 42 peptides and identified that the cellular Ab binding and neurotoxicity were time and concentration dependent. We found a significant correlation between the amount of trimer and tetramer species bound to neurons with increasing neurotoxicity. We prepared A beta 40 oligomers (up to tetramers) using photo-induced cross-linking of unmodified peptides to confirm this oligomer-specific neurotoxic activity. Our results identify the Ab tetramer, followed by the trimer, as the most toxic low-order oligomers Ab species.