The Anti-Amyloid-beta Monoclonal Antibody 4G8 Recognizes a Generic Sequence-Independent Epitope Associated with alpha-Synuclein and Islet Amyloid Polypeptide Amyloid Fibrils

Recently we reported that several monoclonal antibodies that recognize linear segments of amyloid-beta (A beta) also recognize amyloid fibrils, but not monomers of unrelated sequences, indicating that recognition of a linear sequence segment is not a reliable indicator of sequence specificity. We asked whether any of the commonly used commercially available A beta antibodies also recognize fibrils of unrelated sequence. Here we report that 4G8, which recognizes residues 18-23 of the A beta sequence and is widely believed to be sequence-specific, also recognizes fibrils formed from alpha-synuclein and islet amyloid polypeptide (IAPP). The recognition of amyloid fibrils is aggregation-dependent because 4G8 does not recognize alpha-synuclein or IAPP monomer. 4G8 also stains fibrillar alpha-synuclein aggregates in human multiple system atrophy brain where it colocalizes with anti-alpha-synuclein monoclonal antibody LB509 immunoreactivity. We also found that LB509 recognizes A beta fibrils, but not monomer, indicating that generic epitope-reactive antibodies are also produced in response to alpha-synuclein immunization. Taken together, our results indicate that generic fibril conformational epitope specificity may be a pervasive property among monoclonal antibodies raised against amyloid-forming antigens and that the specificity of their immunoreactivity should be rigorously established and otherwise interpreted with caution.