Binding of toxic aoligomers to neuronal cell surface proteins

A3 is a 39-43 residue peptide that accumulates as extracellular aggregates in Alzheimer's afi:lieted brain tissue. Evidence from human genetics, transgenic mice and cell culture strongly suggest a close link between A/3 and Alzheimer's disease tAD) pathogenesis. Interaction between AS and the cell surface is required for toxicity. Synthetic A/3 can form fibrillar structures similar to the deposits seen in AD, which are toxic to neurons in cell culture. However, the contribution of other A species to pathogenesis has been little studied. In the presence of APOJ, an AD-linked protein, or at low aggregation temperatures, A forms soluble toxic oligomers (ADDI,s for A3-Derived Diffusable Ligands). A FA(!S assay was developed to study cell surface binding characteristics of ADl)l,s, using biotinylated 6El0 and HTC-conjugated streptavidin. Cell surface trypsinisation blocks ADDL binding. Tryptie cell surface peptides block ADDL binding but 10% BSA does not indicating that binding is selective for a subset of cell surface protein (s). ADDL binding is blocked by heparin and congo red. Monomeric At31-40 does not block binding. ADDLs bind to both primary neurons and the CNS neuroblstoma B103 cell line, but not yeast cells. Scavenger receptor (SR) is not expressed on neurons, however, blocking assays using the SR ligands fucoidan, dextran sulfate and polyinosinic acid suggest ADDL receptor(s) are SR-like. Identification of neuronal receptors for toxic AI)DLs may provide potential therapeutic targets for the treatment of A]).