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

Amyloid beta (Aß) 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 Aß species remains elusive. We previously reported that Aß 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 Aß species. To identify the specific oligomeric Aß species that is associated with cell death, we treated mouse cortical neuronal cultures with synthetic Aß40 and Aß42 peptides and identified that the cellular Aß 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 Aß40 oligomers (up to tetramers) using photo-induced cross-linking of unmodified peptides to confirm this oligomer-specific neurotoxic activity. Our results identify the Aß tetramer, followed by the trimer, as the most toxic low-order oligomers Aß species. Our findings suggested that binding of amyloid-ß (Aß) tetramer and trimer, not monomer or dimer, to neurons is critical to induce neuronal cell death associated with Alzheimer's Disease. We proposed that Aß trimer and tetramer are the potential neurotoxic Aß species. This would provide more specific therapeutic target for Alzheimer's Disease.