Globular amyloid beta-peptide oligomer - a homogenous and stable neuropathological protein in Alzheimer's disease

Amyloid b-peptide (Ab)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 Ab1)42 oligomer species which can easily be prepared in vitro and is present in the brains of patients with AD and Ab1)42-overproducing transgenic mice. Physicochemical characterization reveals a pure, highly water-soluble globular 60-kDa oligomer which we named ‘Ab1)42 globulomer’. Our data indicate that Ab1)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 Ab1)42 globulomer-specific antibodies that do not cross-react with amyloid precursor protein, Ab1)40 and Ab1)42 monomers and Ab fibrils. Ab1)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 Ab1)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 Ab globulomer structure epitope is expected to have a high potential for