Globular amyloid β-peptide1-42 oligomer -: a homogenous and stable neuropathological protein in Alzheimer's disease

Amyloid beta-peptide (A beta)(1-42) oligomers have recently been discussed as intermediate toxic species in Alzheimer's disease (AD) pathology. Here we describe a new and highly stable A beta(1-42) oligomer species which can easily be prepared in vitro and is present in the brains of patients with AD and A beta(1-42)-overproducing transgenic mice. Physicochemical characterization reveals a pure, highly water-soluble globular 60-kDa oligomer which we named 'A beta(1-42) globulomer'. Our data indicate that A beta(1-42) globulomer is a persistent structural entity formed independently of the fibrillar aggregation pathway. It is a potent antigen in mice and rabbits eliciting generation of A beta(1-42) globulomer-specific antibodies that do not cross-react with amyloid precursor protein, A beta(1-40) and A beta(1-42) monomers and A beta fibrils. A beta(1-42) globulomer binds specifically to dendritic processes of neurons but not glia in hippocampal cell cultures and completely blocks long-term potentiation in rat hippocampal slices. Our data suggest that A beta(1-42) globulomer represents a basic pathogenic structural principle also present to a minor extent in previously described oligomer preparations and that its formation is an early pathological event in AD. Selective neutralization of the A beta globulomer structure epitope is expected to have a high potential for treatment of AD.