The role of cell-derived oligomers of Aβ in Alzheimer's disease and avenues for therapeutic intervention

Burgeoning evidence suggests that soluble oligomers of A beta (amyloid beta-protein) are the earliest effectors of synaptic compromise in Alzheimer's disease. Whereas most other investigators have employed synthetic A beta peptides, we have taken advantage of a alpha-amyloid precursor protein-overexpressing cell line (referred to as 7PA2) that secretes sub-nanomolar levels of low-n oligomers of A beta. These are composed of heterogeneous A beta peptides that migrate on SDS/PAGE as dimers, trimers and tetramers. When injected into the lateral ventricle of rats in vivo, these soluble oligomers inhibit hippocampal long-term potentiation and alter the memory of a complex learned behaviour. Biochemical manipulation of 7PA2 medium including immunodepletion with A beta-specific antibodies and fractionation by size-exclusion chromatography allowed us to unambiguously attribute these effects to low-n oligomers. Using this paradigm we have tested compounds directed at three prominent amyloid-based therapeutic targets: inhibition of the secretases responsible for A beta production, inhibition of A beta aggregation and immunization against A beta. In each case, compounds capable of reducing oligomer production or antibodies that avidly bind A beta oligomers also ameliorate the synaptotoxic effects of these natural, cell-derived oligomers.